which in turn promotes Treg suppression [397]. Titrata-
tion of this signaling axis modulates immune tolerance,
applying that upstream inhibition of PI3K may dis-
rupt tumor immune tolerance [398]. Additionally, it has
recently been shown that inhibitory signaling through
PD-1 restricts activation of Treg-mediated immunosup-
pression in an AKT-dependent manner [399]. Moreo-
ver, AKT is also known to modify myeloid cell fate and
survival through its regulation of β-catenin, NF-κB sign-
aling, and cytokine production [400]. Furthermore, iso-
form-dependent AKT signaling is a key determinant of
M1/M2 macrophage polarization [401, 402], and AKT
is required for the maturation of bone marrow-derived
dendritic cells [403]. mTOR-mediated regulation of
the immune system is complex and is comprehensively
reviewed elsewhere [404, 405]. mTOR is the catalytic
domain of the complementary mTORC1 and mTORC2
complexes. These complexes co-regulate cellular metabo-
lism, the primary mechanism by which mTOR regulates
the immune system, as mobilizing immune cells is ener-
getically expensive and requires metabolic reconfigura-
tion. mTORC1, in particular, has been shown to regulate
memory T-cell differentiation [406] and establish the
function of immunosuppressive Tregs [407]. Therefore,
even though rapamycin-induced inhibition of mTORC1
promotes Treg development from naïve T-cells [408]
and subsequent Treg expansion [409, 410], rapamycin
can still promote autoimmunity through the suppres-
sion of Treg function [407]. The role of mTORC2 is more
subtle, but it has been shown to play an inhibitory role
in the generation of CD8+memory T-cells, driven by
mTORC2-induced inhibition of FOXO-mediated IL-15R
expression [411]. Importantly, mTORC1 and mTORC2
are also directly involved in regulating innate immunity.
mTORC1 controls monocyte/macrophage-mediated
inflammation by regulating production of inflammatory
cytokines via inhibition of NF-κB (downstream PI3Kγ) [412]. Again, mTORC2 plays a complementary role,
modifying chemotaxis in mast cells and neutrophils.
Besides, mTORC2 downregulates IL-12 in dendritic cells,
due to inhibition of FOXO1 [413], and plays an important
role in IL-4-dependent, alternative activation of M2 mac-
rophages [414, 415]. Cancer cell-autonomous activation
of PAM signaling has been shown to promote expres-
sion of immunosuppressive cytokines, chemokines, and
immune checkpoints, which can be reversed through
pharmacologic inhibition of PAM signaling [416]. mTOR
regulates the expression of inflammatory cytokines such
as IL-10, IL-12, TGF-β, and TNF [417, 418]. Activation
of neoplastic PAM signaling also promotes expression
of vascular endothelial growth factor (VEGF), an impor-
tant mediator of angiogenic signaling that also acts as a
chemoattractant of immunosuppressive MDSCs [419]

and Tregs [420]. Reciprocally, inhibition of mTOR with
everolimus, has been shown to partially phenocopy the
anti-angiogenic effect of VEGF inhibitors [421]. Moreo-
ver, due to the role of PAM and especially mTOR in
metabolic regulation, PAM inhibition within nutrient-
constrained tumor microenvironments can disrupt the
balance between CD4+/CD8+T-cells, Tregs/T helper
17 (Th17) cells, and M1/M2 macrophages [417]. Finally,
many studies have associated activated PAM signaling
with increased PD-L1 expression [422, 423], and PAM
inhibition has been shown to be capable of reducing
PD-L1 expression in PTEN-driven breast and CRC cells
[424].

Targeting PAM Signaling alongside immunotherapy

Over the last decade, the treatment of cancer has been
revolutionized by the introduction of immunotherapies.
New agents that target the PD-1/PD-L1 and CTLA-4
immune checkpoints, known as immune checkpoint
inhibitors (ICIs), and cellular therapies designed to seek
out cancer cells, have demonstrated remarkable effi-
cacy. Yet, despite these successes, many cancers do not
respond or respond incompletely to immunotherapy,
underscoring the importance of better understanding the
mechanisms underlying the resistance to these agents.

Immune checkpoint inhibitors (ICIs)

Many of the mechanisms that underlie ICI treatment
failure, including defective neoantigen presentation,
T-cell resistance, excess immunosuppressive cytokines,
and intratumoral inhibitory MDSCs or Tregs [425], are
associated with PAM signaling; and thus, may be revers-
able with PAM inhibition. Indeed, there is increasing
evidence that targeting the PAM pathway can reduce
the production of immunosuppressive cytokines and
restrict the proliferation and penetration of immunosup-
pressive Tregs and MDSCs, thereby boosting the anti-
tumor effects of immune checkpoint blockade [389, 426,
427]. Activation of oncogenic pathways like PAM and
MAPK promote transcriptional upregulation of neo-
plastic PD-L1. Accordingly, therapies targeting PAM and
upstream kinase signaling have been shown to reduce
intrinsic neoplastic PD-L1 expression. In PTEN-driven
murine models of melanoma, the efficacy of both anti-
PD-1 and anti-CTLA-4 antibodies has been improved
by co-inhibition of PI3K [427]. In syngeneic and genet-
ically-engineered mouse models of lung cancer, inhibi-
tion of mTOR bolsters the effects of PD-1 blockade [422].
Similar results have been reported with anti-PD-1 and
anti-CTLA-4 therapies in breast cancer [428]. Combin-
ing PAM inhibition with ICI treatment decreases Treg
populations and enhances the CD8+memory T-cell
response in murine models and in vitro patient cell assays
[429]. Many early-phase clinical studies have been test-
ing the aforementioned principles by assessing the tol-
erability and efficacy of combined PAM inhibition and
immune checkpoint inhibition, primarily in advanced
solid tumors, and lymphomas [430, 206]. Some of these
clinical trials are highlighted below. Phase 1/2 clini-
cal trial NCT03131908 is studying the combination of
PD-1 inhibitor pembrolizumab and PI3Kβ inhibitor
GSK2636771 in PD-1 refractory patients with meta-
static melanoma and PTEN loss [431]. Besides, phase 1/2
clinical trial NCT04688658 is focussing on the combina-
tion of PD-1 inhibitor nivolumab and PI3Kδγ inhibitor
duvelisib in patients with unresectable melanoma that
have already progressed on PD-1 therapy, with clinical
response in at least one patient in preliminary results
[432]. Moreover, phase 2 clinical trial NCT03484819 is
evaluating the combination of nivolumab and PI3Kαδ
inhibitor copanlisib in relapsed/refractory diffuse large
B-cell lymphoma or primary mediastinal large B-cell
lymphoma. This clinical study is also trying to character-
ize the effects of this combination on the tumor micro-
environment and immune response [433]. Furthermore,
phase 1 clinical trial (NCT03884998) is investigating the
the combination of nivolumab and pan-PI3K inhibitor
copanlisib in patients with Richter's transformation, with
to date a favorable safety profile [434].

Chimeric antigen receptor (CAR) T-cell therapy

Another emerging pillar of immunotherapy is cellular
therapy, particularly chimeric antigen receptor (CAR)
T-cell therapy, where synthetically-engineered recep-
tors direct pre-harvested T-cells to cancer cells express-
ing a select antigen. There is evidence that PAM-directed
therapies could serve as a novel modifier to CAR-T cell
therapy, possibly at the point of treatment [435], but pri-
marily as a cell culture additive during T-cell expansion
[430, 436]. Mechanistically, it is reported that anti-CD3/
CD28 stimulation of T-cell receptor during CAR T-cell
manufacturing process induces PAM signaling, result-
ing in terminal T-cell differentiation and decreased CAR
T-cell persistence [430]. Earlier studies associate PAM
activation with CAR T-cell decreased persistence and
showed that PI3K inhibition with the non-selective PI3K
inhibitor LY294002 was able to restrict CAR T-cell differ-
entiation. This enables the maintenance of a less-differen-
tiated state and ultimately improving persistence in vivo
[437]. Subsequently, other groups have shown that tar-
geted PI3K inhibition, focusing on the PI3Kγ and PI3Kδ
isoforms, is capable of decreasing the expression of T-cell
exhaustion markers PD-1 and Tim-3 while upregulating
the lymph node homing marker CD62L [438], decreasing
the expression of immune checkpoints, and increasing

the yield of T-stem cell memory and central memory
CD8+CAR T-cells [439, 440]. These initial observa-
tions in CAR T-cell therapy may also be applicable to the
growing field of bispecific antibodies, some of which have
recently been approved for the treatment of B-cell non-
Hodgkin's lymphomas.

Conclusion

PI3K inhibition is considered a major target for antitumor therapy. Unfortunately, past and present clinical trials using PI3Ki have exhibited modest anticancer activity mainly due to resistance to PI3K inhibition and insufficient target inhibition at tolerated doses. Indeed, over the last few decades, pan-PI3Ki and dual PI3K/mTORi, not only have demonstrated limited efficacy but also are associated with significant side effects. As a result, few PI3Ki have been approved by the FDA. Since selective isoforms of PI3K perform pivotal functions in the biology of specific cancer subtypes, the present-day focus is centered on the development of IS PI3Ki. Of late, IS PI3Ki have shown promising results in several clinical trials, largely exhibiting better target specificity and toxicity profiles as compared to conventional pan-PI3Ki and/or dual PI3K/mTORi. PAM pathway inhibitors have produced limited therapeutic efficacy and significant treatment-related toxicity particularly when combined with standard treatments or other targeted agents. Hence, most PAM pathway inhibitors are unsuitable for adoption as mainstream oncological treatment strategies. For this reason, combination therapy with two or more agents in conjunction with other therapeutic strategies, such as surgery, hormonal therapy, and other antitumor drugs, has been the trend in recent years. In line with this, combination of PI3Ki with ncRNAs, or inhibitors of crucial signaling nodes in other cross-interacting pathways, may represent a future approach to effectively suppress the PAM pathway, whilst minimizing the risk of developing drug resistance and occurrence of adverse events. In future studies it would be ideal to identify stable biomarkers for patient stratification, according to cancer types and genetic profiles, to better benefit from PI3K inhibition. The mechanism exerted by PI3Ki has not been thoroughly elucidated, and will require further studies to properly delineate its pros and cons as part of the endeavour to personalize oncological therapeutics. The design of novel PI3K inhibitors structurally-based on different binding sites would undoubtedly improve specificity, and reduce toxicity of IS PI3Ki. Therefore, demystifying the mechanisms of PI3K signaling and PI3K inhibition is essential to improve combination strategy, and patient selection, which would in turn enhance the efficacy of these cancer drugs.
[429]. Many early-phase clinical studies have been test-
ing the aforementioned principles by assessing the tol-
erability and efficacy of combined PAM inhibition and
immune checkpoint inhibition, primarily in advanced
solid tumors, and lymphomas [430, 206]. Some of these
clinical trials are highlighted below. Phase 1/2 clini-
cal trial NCT03131908 is studying the combination of
PD-1 inhibitor pembrolizumab and PI3Kβ inhibitor
GSK2636771 in PD-1 refractory patients with meta-
static melanoma and PTEN loss [431]. Besides, phase 1/2
clinical trial NCT04688658 is focussing on the combina-
tion of PD-1 inhibitor nivolumab and PI3Kδγ inhibitor
duvelisib in patients with unresectable melanoma that
have already progressed on PD-1 therapy, with clinical
response in at least one patient in preliminary results
[432]. Moreover, phase 2 clinical trial NCT03484819 is
evaluating the combination of nivolumab and PI3Kαδ
inhibitor copanlisib in relapsed/refractory diffuse large
B-cell lymphoma or primary mediastinal large B-cell
lymphoma. This clinical study is also trying to character-
ize the effects of this combination on the tumor micro-
environment and immune response [433]. Furthermore,
phase 1 clinical trial (NCT03884998) is investigating the
the combination of nivolumab and pan-PI3K inhibitor
copanlisib in patients with Richter's transformation, with
to date a favorable safety profile [434].

Chimeric antigen receptor (CAR) T-cell therapy

Another emerging pillar of immunotherapy is cellular
therapy, particularly chimeric antigen receptor (CAR)
T-cell therapy, where synthetically-engineered recep-
tors direct pre-harvested T-cells to cancer cells express-
ing a select antigen. There is evidence that PAM-directed
therapies could serve as a novel modifier to CAR-T cell
therapy, possibly at the point of treatment [435], but pri-
marily as a cell culture additive during T-cell expansion
[430, 436]. Mechanistically, it is reported that anti-CD3/
CD28 stimulation of T-cell receptor during CAR T-cell
manufacturing process induces PAM signaling, result-
ing in terminal T-cell differentiation and decreased CAR
T-cell persistence [430]. Earlier studies associate PAM
activation with CAR T-cell decreased persistence and
showed that PI3K inhibition with the non-selective PI3K
inhibitor LY294002 was able to restrict CAR T-cell differ-
entiation. This enables the maintenance of a less-differen-
tiated state and ultimately improving persistence in vivo
[437]. Subsequently, other groups have shown that tar-
geted PI3K inhibition, focusing on the PI3Kγ and PI3Kδ
isoforms, is capable of decreasing the expression of T-cell
exhaustion markers PD-1 and Tim-3 while upregulating
the lymph node homing marker CD62L [438], decreasing
the expression of immune checkpoints, and increasing

the yield of T-stem cell memory and central memory
CD8+CAR T-cells [439, 440]. These initial observa-
tions in CAR T-cell therapy may also be applicable to the
growing field of bispecific antibodies, some of which have
recently been approved for the treatment of B-cell non-
Hodgkin's lymphomas.

Conclusion

PI3K inhibition is considered a major target for antitumor therapy. Unfortunately, past and present clinical trials using PI3Ki have exhibited modest anticancer activity mainly due to resistance to PI3K inhibition and insufficient target inhibition at tolerated doses. Indeed, over the last few decades, pan-PI3Ki and dual PI3K/mTORi, not only have demonstrated limited efficacy but also are associated with significant side effects. As a result, few PI3Ki have been approved by the FDA. Since selective isoforms of PI3K perform pivotal functions in the biology of specific cancer subtypes, the present-day focus is centered on the development of IS PI3Ki. Of late, IS PI3Ki have shown promising results in several clinical trials, largely exhibiting better target specificity and toxicity profiles as compared to conventional pan-PI3Ki and/or dual PI3K/mTORi. PAM pathway inhibitors have produced limited therapeutic efficacy and significant treatment-related toxicity particularly when combined with standard treatments or other targeted agents. Hence, most PAM pathway inhibitors are unsuitable for adoption as mainstream oncological treatment strategies. For this reason, combination therapy with two or more agents in conjunction with other therapeutic strategies, such as surgery, hormonal therapy, and other antitumor drugs, has been the trend in recent years. In line with this, combination of PI3Ki with ncRNAs, or inhibitors of crucial signaling nodes in other cross-interacting pathways, may represent a future approach to effectively suppress the PAM pathway, whilst minimizing the risk of developing drug resistance and occurrence of adverse events. In future studies it would be ideal to identify stable biomarkers for patient stratification, according to cancer types and genetic profiles, to better benefit from PI3K inhibition. The mechanism exerted by PI3Ki has not been thoroughly elucidated, and will require further studies to properly delineate its pros and cons as part of the endeavour to personalize oncological therapeutics. The design of novel PI3K inhibitors structurally-based on different binding sites would undoubtedly improve specificity, and reduce toxicity of IS PI3Ki. Therefore, demystifying the mechanisms of PI3K signaling and PI3K inhibition is essential to improve combination strategy, and patient selection, which would in turn enhance the efficacy of these cancer drugs.
Inhibition of AKT can potentially exert remarkable
antineoplastic effects, although dose-limiting toxicity
and insufficient knowledge of the different isoforms have
impeded its successful pharmacological usage. Indeed,
pharmacodynamic markers of AKT inhibitors have
shown incomplete target modulation. Nowadays, there
are no approved biomarkers that can predict therapeu-
tic responses to specific AKT inhibitors before using a
particular agent. Thus, it is not possible to predict which
patients can have adverse effects from AKT inhibition.
Targeting AKT is considered a critical research area in
clinical oncology, and possibly, in future studies, AKT
inhibitors in combination with synergistic cytotoxic
drugs could probably improve their clinical efficacy.

Several classes of mTORi have been developed, but only everolimus and temsirolimus have obtained approval as therapy for human tumors. The clinical application of these agents is impeded by resistance determined through a variety of molecular mechanisms common to the different class of drugs, suggesting that co-targeting alternative pathways may be a more feasible strategy than improving the action of mTORi. Importantly, pre-clinical and clinical data suggest that novel bi-steric mTORi can drive cancer regression more significantly compared to other mTORi, by enhancing inhibition of 4E-BP1 phosphorylation, and reducing adaptive resistance due to the relief of feedback inhibition of RTK expression. Thus, bi-steric mTORi may be the most promising inhibitors in treating activated mTORC1-driven cancers. Also, developing novel therapeutic combinations could lead to the identification of molecular factors resistant to each class of drugs to improve the selection of patients who may benefit from a specific treatment. Besides, optimisation of treatment sequence using different agents may be useful to delay or overcome resistance to mTOR inhibitors.

Additionally, PAM signaling exert a fine control over
the immune system-mediated functions, including anti-
tumor response. Ongoing studies are evaluating the
impact of PAM-targeted treatments on cancer response,
immune reaction and their synergy with immune-based
cancer therapies.

The potential of PAM inhibitors clearly depends on the
combinatorial strategies. However, the main difficulties
are: 1) defining the ideal combination for each patient,
and 2) managing toxicity of combination approaches that
necessitate innovative scheduling. In addition, the bio-
marker development is challenged by the complex inter-
actions of the pathway and in general multiple co-existing
alterations that help to maintain cancer survival. Finally,
we must also improve our understanding of the effects
determined by PAM signaling pathway inhibitors on the
tumour microenvironment for plausible drug combina-
tions with specific immunotherapies.

Abbreviations

<table>
   <tr>
    <td>
     CAR
    </td>
    <td>
     Chimeric antigen receptor
    </td>
   </tr>
   <tr>
    <td>
     CLL
    </td>
    <td>
     Chronic lymphocytic leukemia
    </td>
   </tr>
   <tr>
    <td>
     CRC
    </td>
    <td>
     Colorectal cancer
    </td>
   </tr>
   <tr>
    <td>
     EGFR
    </td>
    <td>
     Epidermal growth factor receptor (ERBB)
    </td>
   </tr>
   <tr>
    <td>
     EMT
    </td>
    <td>
     Epithelial-mesenchymal transition
    </td>
   </tr>
   <tr>
    <td>
     ER
    </td>
    <td>
     Estrogen receptor
    </td>
   </tr>
   <tr>
    <td>
     FDA
    </td>
    <td>
     Food and Drug Administration
    </td>
   </tr>
   <tr>
    <td>
     FGFR
    </td>
    <td>
     Fibroblast growth factor receptor
    </td>
   </tr>
   <tr>
    <td>
     FRB
    </td>
    <td>
     FKBP12-rapamycin-binding
    </td>
   </tr>
   <tr>
    <td>
     HGF
    </td>
    <td>
     Hepatocyte growth factor
    </td>
   </tr>
   <tr>
    <td>
     HNSCC
    </td>
    <td>
     Head and neck squamous cell cancer
    </td>
   </tr>
   <tr>
    <td>
     HR
    </td>
    <td>
     Hormone receptor
    </td>
   </tr>
   <tr>
    <td>
     ICIs
    </td>
    <td>
     Immune checkpoint inhibitors
    </td>
   </tr>
   <tr>
    <td>
     IGF1
    </td>
    <td>
     Insulin-like growth factor 1
    </td>
   </tr>
   <tr>
    <td>
     INSR
    </td>
    <td>
     Insulin receptor
    </td>
   </tr>
   <tr>
    <td>
     IRS1
    </td>
    <td>
     Insulin receptor substrate 1
    </td>
   </tr>
   <tr>
    <td>
     LTK
    </td>
    <td>
     Leukocyte receptor tyrosine kinase
    </td>
   </tr>
   <tr>
    <td>
     MCL
    </td>
    <td>
     Mantle cell lymphoma
    </td>
   </tr>
   <tr>
    <td>
     MDSCs
    </td>
    <td>
     Myeloid-derived suppressor cells
    </td>
   </tr>
   <tr>
    <td>
     MCL
    </td>
    <td>
     Mantle cell lymphoma
    </td>
   </tr>
   <tr>
    <td>
     MZL
    </td>
    <td>
     Marginal zone lymphoma
    </td>
   </tr>
   <tr>
    <td>
     NET
    </td>
    <td>
     Neuroendocrine tumor
    </td>
   </tr>
   <tr>
    <td>
     NSCLC
    </td>
    <td>
     Non-small-cell lung cancer
    </td>
   </tr>
   <tr>
    <td>
     ORR
    </td>
    <td>
     Overall response rate
    </td>
   </tr>
   <tr>
    <td>
     PAM
    </td>
    <td>
     PI3K/AKT/mTOR
    </td>
   </tr>
   <tr>
    <td>
     PDGFR
    </td>
    <td>
     Platelet-derived growth factor receptor
    </td>
   </tr>
   <tr>
    <td>
     RCC
    </td>
    <td>
     Renal cell carcinoma
    </td>
   </tr>
   <tr>
    <td>
     SCLC
    </td>
    <td>
     Small-cell lung cancer
    </td>
   </tr>
   <tr>
    <td>
     SEGA
    </td>
    <td>
     Subependymal giant cell astrocytoma
    </td>
   </tr>
   <tr>
    <td>
     SLL
    </td>
    <td>
     Small lymphocytic lymphoma
    </td>
   </tr>
   <tr>
    <td>
     TCR
    </td>
    <td>
     T-cell receptor
    </td>
   </tr>
   <tr>
    <td>
     Tregs
    </td>
    <td>
     Regulatory T-cells
    </td>
   </tr>
   <tr>
    <td>
     VEGF
    </td>
    <td>
     Vascular endothelial growth factor
    </td>
   </tr>
   <tr>
    <td>
     VEGFR
    </td>
    <td>
     Vascular endothelial growth factor receptor
    </td>
   </tr>
  </table>

**Supplementary Information**

The online version contains supplementary material available at https://doi.
org/10.1186/s12943-023-01827-6.

Additional file 1: Supplementary figure 1.

Additional file 2: Supplementary information 1.

Additional file 3: Supplementary information 2.

Additional file 4: Supplementary information 3.

Additional file 5: Supplementary table 1.

Additional file 6: Supplementary table 2.

Additional file 7: Supplementary table 3.

Acknowledgements

H.E. is supported by a NUS Medicine Postdoctoral Fellowship funded by the Ministry of Education (MOE) and the Social Sciences Research Council (SSRC) of Singapore. D.B.L.T. is supported by grants from the Singapore National Medical Council (A-0006179-00-00—NMRC OF YIRG) and from the Singapore Ministry of Education (A-0006237-00-00—MOE GAP Funding). BG is supported by the Medecin-Chercheur Parrainage program of Gustave Roussy Cancer Center. The mTOR inhibitor research in the laboratory of D.A.F. is supported by a Reach Grant from Alex's Lemonade Stand Foundation.

Authors' contributions

A.G and A.P.K. conceptualized the manuscript topic; A.G., J.S., D.A.F., and A.P.K. collated literature for the manuscript; A.G. wrote the manuscript; A.S.C.F., H.Y.L., K.C.H.Y., W.J., R.H.J., H.E., M.G.N., P.M., B.G., M.H.K., R.D.B., J.S.P., D.C., C.P., D.B.L.T., G.S., V.C., K.H.L., N.R.J.S., E.T., M.S.D., J.R.B., P.D., J.S., D.A.F., and A.P.K. edited the manuscript; A.G. designed the figures; A.G., E.T., M.S.D., J.R.B., P.D., J.S., D.A.F and A.P.K. finalized the manuscript. All authors have read and agreed to the submitted version of the manuscript.
Inhibition of AKT can potentially exert remarkable
antineoplastic effects, although dose-limiting toxicity
and insufficient knowledge of the different isoforms have
impeded its successful pharmacological usage. Indeed,
pharmacodynamic markers of AKT inhibitors have
shown incomplete target modulation. Nowadays, there
are no approved biomarkers that can predict therapeu-
tic responses to specific AKT inhibitors before using a
particular agent. Thus, it is not possible to predict which
patients can have adverse effects from AKT inhibition.
Targeting AKT is considered a critical research area in
clinical oncology, and possibly, in future studies, AKT
inhibitors in combination with synergistic cytotoxic
drugs could probably improve their clinical efficacy.

Several classes of mTORi have been developed, but only everolimus and temsirolimus have obtained approval as therapy for human tumors. The clinical application of these agents is impeded by resistance determined through a variety of molecular mechanisms common to the different class of drugs, suggesting that co-targeting alternative pathways may be a more feasible strategy than improving the action of mTORi. Importantly, pre-clinical and clinical data suggest that novel bi-steric mTORi can drive cancer regression more significantly compared to other mTORi, by enhancing inhibition of 4E-BP1 phosphorylation, and reducing adaptive resistance due to the relief of feedback inhibition of RTK expression. Thus, bi-steric mTORi may be the most promising inhibitors in treating activated mTORC1-driven cancers. Also, developing novel therapeutic combinations could lead to the identification of molecular factors resistant to each class of drugs to improve the selection of patients who may benefit from a specific treatment. Besides, optimisation of treatment sequence using different agents may be useful to delay or overcome resistance to mTOR inhibitors.

Additionally, PAM signaling exert a fine control over
the immune system-mediated functions, including anti-
tumor response. Ongoing studies are evaluating the
impact of PAM-targeted treatments on cancer response,
immune reaction and their synergy with immune-based
cancer therapies.

The potential of PAM inhibitors clearly depends on the
combinatorial strategies. However, the main difficulties
are: 1) defining the ideal combination for each patient,
and 2) managing toxicity of combination approaches that
necessitate innovative scheduling. In addition, the bio-
marker development is challenged by the complex inter-
actions of the pathway and in general multiple co-existing
alterations that help to maintain cancer survival. Finally,
we must also improve our understanding of the effects
determined by PAM signaling pathway inhibitors on the
tumour microenvironment for plausible drug combina-
tions with specific immunotherapies.

Abbreviations

<table>
   <tr>
    <td>
     CAR
    </td>
    <td>
     Chimeric antigen receptor
    </td>
   </tr>
   <tr>
    <td>
     CLL
    </td>
    <td>
     Chronic lymphocytic leukemia
    </td>
   </tr>
   <tr>
    <td>
     CRC
    </td>
    <td>
     Colorectal cancer
    </td>
   </tr>
   <tr>
    <td>
     EGFR
    </td>
    <td>
     Epidermal growth factor receptor (ERBB)
    </td>
   </tr>
   <tr>
    <td>
     EMT
    </td>
    <td>
     Epithelial-mesenchymal transition
    </td>
   </tr>
   <tr>
    <td>
     ER
    </td>
    <td>
     Estrogen receptor
    </td>
   </tr>
   <tr>
    <td>
     FDA
    </td>
    <td>
     Food and Drug Administration
    </td>
   </tr>
   <tr>
    <td>
     FGFR
    </td>
    <td>
     Fibroblast growth factor receptor
    </td>
   </tr>
   <tr>
    <td>
     FRB
    </td>
    <td>
     FKBP12-rapamycin-binding
    </td>
   </tr>
   <tr>
    <td>
     HGF
    </td>
    <td>
     Hepatocyte growth factor
    </td>
   </tr>
   <tr>
    <td>
     HNSCC
    </td>
    <td>
     Head and neck squamous cell cancer
    </td>
   </tr>
   <tr>
    <td>
     HR
    </td>
    <td>
     Hormone receptor
    </td>
   </tr>
   <tr>
    <td>
     ICIs
    </td>
    <td>
     Immune checkpoint inhibitors
    </td>
   </tr>
   <tr>
    <td>
     IGF1
    </td>
    <td>
     Insulin-like growth factor 1
    </td>
   </tr>
   <tr>
    <td>
     INSR
    </td>
    <td>
     Insulin receptor
    </td>
   </tr>
   <tr>
    <td>
     IRS1
    </td>
    <td>
     Insulin receptor substrate 1
    </td>
   </tr>
   <tr>
    <td>
     LTK
    </td>
    <td>
     Leukocyte receptor tyrosine kinase
    </td>
   </tr>
   <tr>
    <td>
     MCL
    </td>
    <td>
     Mantle cell lymphoma
    </td>
   </tr>
   <tr>
    <td>
     MDSCs
    </td>
    <td>
     Myeloid-derived suppressor cells
    </td>
   </tr>
   <tr>
    <td>
     MCL
    </td>
    <td>
     Mantle cell lymphoma
    </td>
   </tr>
   <tr>
    <td>
     MZL
    </td>
    <td>
     Marginal zone lymphoma
    </td>
   </tr>
   <tr>
    <td>
     NET
    </td>
    <td>
     Neuroendocrine tumor
    </td>
   </tr>
   <tr>
    <td>
     NSCLC
    </td>
    <td>
     Non-small-cell lung cancer
    </td>
   </tr>
   <tr>
    <td>
     ORR
    </td>
    <td>
     Overall response rate
    </td>
   </tr>
   <tr>
    <td>
     PAM
    </td>
    <td>
     PI3K/AKT/mTOR
    </td>
   </tr>
   <tr>
    <td>
     PDGFR
    </td>
    <td>
     Platelet-derived growth factor receptor
    </td>
   </tr>
   <tr>
    <td>
     RCC
    </td>
    <td>
     Renal cell carcinoma
    </td>
   </tr>
   <tr>
    <td>
     SCLC
    </td>
    <td>
     Small-cell lung cancer
    </td>
   </tr>
   <tr>
    <td>
     SEGA
    </td>
    <td>
     Subependymal giant cell astrocytoma
    </td>
   </tr>
   <tr>
    <td>
     SLL
    </td>
    <td>
     Small lymphocytic lymphoma
    </td>
   </tr>
   <tr>
    <td>
     TCR
    </td>
    <td>
     T-cell receptor
    </td>
   </tr>
   <tr>
    <td>
     Tregs
    </td>
    <td>
     Regulatory T-cells
    </td>
   </tr>
   <tr>
    <td>
     VEGF
    </td>
    <td>
     Vascular endothelial growth factor
    </td>
   </tr>
   <tr>
    <td>
     VEGFR
    </td>
    <td>
     Vascular endothelial growth factor receptor
    </td>
   </tr>
  </table>

**Supplementary Information**

The online version contains supplementary material available at https://doi.
org/10.1186/s12943-023-01827-6.

Additional file 1: Supplementary figure 1.

Additional file 2: Supplementary information 1.

Additional file 3: Supplementary information 2.

Additional file 4: Supplementary information 3.

Additional file 5: Supplementary table 1.

Additional file 6: Supplementary table 2.

Additional file 7: Supplementary table 3.

Acknowledgements

H.E. is supported by a NUS Medicine Postdoctoral Fellowship funded by the Ministry of Education (MOE) and the Social Sciences Research Council (SSRC) of Singapore. D.B.L.T. is supported by grants from the Singapore National Medical Council (A-0006179-00-00—NMRC OF YIRG) and from the Singapore Ministry of Education (A-0006237-00-00—MOE GAP Funding). BG is supported by the Medecin-Chercheur Parrainage program of Gustave Roussy Cancer Center. The mTOR inhibitor research in the laboratory of D.A.F. is supported by a Reach Grant from Alex's Lemonade Stand Foundation.

**Authors’ contributions**

A.G and A.P.K. conceptualized the manuscript topic; A.G., J.S., D.A.F., and A.P.K. collated literature for the manuscript; A.G. wrote the manuscript; A.S.C.F., H.Y.L., K.C.H.Y., W.J., R.H.J., H.E., M.G.N., P.M., B.G., M.H.K., R.D.B., J.S.P., D.C., C.P., D.B.L.T., G.S., V.C., K.H.L., N.R.J.S., E.T., M.S.D., J.R.B., P.D., J.S., D.A.F., and A.P.K. edited the manuscript; A.G. designed the figures; A.G., E.T., M.S.D., J.R.B., P.D., J.S., D.A.F and A.P.K. finalized the manuscript. All authors have read and agreed to the submitted version of the manuscript.
## Funding

A.P.K. was supported by a grant from the Singapore Ministry of Education (MOE-T2EP30120-0016).

## Availability of data and materials

Not applicable.

## Declarations

### Ethics approval and consent to participate

Not applicable.

### Competing interests

The authors declare no competing interests.

Received: 21 May 2023 Accepted: 18 July 2023

Published online: 18 August 2023

## References

1. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-74.

2. Tian LY, Smit DJ, Jücker M. The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism. Int J Mol Sci. 2023;24(3):2652.

3. Ahmad I, Hoque M, Alam SSM, Zugaibi TA, Tabrez S. Curcumin and Plumbagin Synergistically Target the PI3K/Akt/mTOR Pathway: A Prospective Role in Cancer Treatment. Int J Mol Sci. 2023;24(7):6651.

4. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273-91.

5. Mohan CD, Srinivasa V, Rangappa S, Mervin L, Mohan S, Paricharak S, et al. Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway. PLoS ONE. 2016;11(4):e0153155.

6. Lee JH, Chinnathambi A, Alharbi SA, Shair OHM, Sethi G, Ahn KS. Farnesol abrogates epithelial to mesenchymal transition process through regulating Akt/mTOR pathway. Pharmacol Res. 2019;150: 104504.

7. Tewari D, Patni P, Bishayee A, Sah AN. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy. Semin Cancer Biol. 2022;80:1-17.

8. Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74-88.

9. Yang MH, Lee JH, Ko JH, Jung SH, Sethi G, Ahn KS. Brassinin Represses Invasive Potential of Lung Carcinoma Cells through Deactivation of PI3K/Akt/mTOR Signaling Cascade. Molecules. 2019;24(8):1584.

10. Siveen KS, Ahn KS, Ong TH, Shanmugam MK, Li F, Yap WN, et al. Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget. 2014;5(7):1897-911.

11. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988-1004.

12. Lee JH, Kim C, Um JY, Sethi G, Ahn KS. Casticin-Induced Inhibition of Cell Growth and Survival Are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade. Cancers (Basel). 2019;11(2):254.

13. Ong PS, Wang LZ, Dai X, Tseng SH, Loo SJ, Sethi G. Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Front Pharmacol. 2016;7:395.

14. Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46(6):372-83.

15. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495-501.

16. Turdo A, D'Accardo C, Glaviano A, Porcelli G, Colarossi C, Colarossi L, et al. Targeting Phosphatases and Kinases: How to Checkmate Cancer. Front Cell Dev Biol. 2021;9:690306.

17. Yuan Y, Long H, Zhou Z, Fu Y, Jiang B. PI3K-AKT-Targeting Breast Cancer Treatments: Natural Products and Synthetic Compounds. Biomolecules. 2023;13(1):93.

18. Zhu K, Wu Y, He P, Fan Y, Zhong X, Zheng H, et al. PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer. Cells. 2022;11(16):2508.

19. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489-501.

20. Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol. 2022;85:69-94.

21. Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY, et al. HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. J Biol Chem. 2000;275(11):8027-31.

22. Dillon RL, White DE, Muller WJ. The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene. 2007;26(9):1338-45.

23. Zhang Y, Kwok-Shing Ng P, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell. 2017;31(6):820-32.e3.

24. Ko JH, Um JY, Lee SG, Yang WM, Sethi G, Ahn KS. Conditioned media from adipocytes promote proliferation, migration, and invasion in melanoma and colorectal cancer cells. J Cell Physiol. 2019;234(10):18249-61.

25. Ashrafizadeh M, Zarrabi A, Hushmandi K, Kalantari M, Moham-adinejad R, Javaheri T, et al. Association of the Epithelial-Mesenchymal Transition (EMT) with Cisplatin Resistance. Int J Mol Sci. 2020;21(11):4002.

26. Deng J, Bai X, Feng X, Ni J, Beretov J, Graham P, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer. 2019;19(1):618.

27. Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? Front Oncol. 2022;12:819128.

28. Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016;6(10):1090-105.

29. Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20(10):741-69.

30. Castel P, Toska E, Engelman JA, Scaltriti M. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer. 2021;2(6):587-97.

31. Vasan N, Toska E, Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol. 2019;30(Suppl_10):x3-11.

32. Vasan N, Cantley LC. At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy. Nat Rev Clin Oncol. 2022;19(7):471-85.

33. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160-74.

34. Law NC, White MF, Hunzicker-Dunn ME. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway. J Biol Chem. 2019;291(53):27160-9.

35. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11(5):329-41.

36. Lyu H, Han A, Polsdofer E, Liu S, Liu B. Understanding the biology of HER3 receptor as a therapeutic target in human cancer. Acta Pharm Sin B. 2018;8(4):503-10.

37. Sidorov M, Dighe P, Woo RWL, Rodriguez-Brotons A, Chen M, Ice RJ, et al. Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment. Cells. 2023;12(4):547.

38. Babina IS, Turner NC. Advances and challenges in targeting FGFR signaling in cancer. Nat Rev Cancer. 2017;17(5):318-32.

39. Brown LM, Ekert PG, Fleuren EDG. Biological and clinical implications of FGFR aberrations in paediatric and young adult cancers. Oncogene. 2023;42(23):1875-88.

40. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRα activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-10.
Funding

A.P.K. was supported by a grant from the Singapore Ministry of Education (MOE-T2EP30120-0016).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Received: 21 May 2023 Accepted: 18 July 2023

Published online: 18 August 2023

References

1. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-74.

2. Tian LY, Smit DJ, Jücker M. The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism. Int J Mol Sci. 2023;24(3):2652.

3. Ahmad I, Hoque M, Alam SSM, Zugaibi TA, Tabrez S. Curcumin and Plumbagin Synergistically Target the PI3K/Akt/mTOR Pathway: A Prospective Role in Cancer Treatment. Int J Mol Sci. 2023;24(7):6651.

4. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273-91.

5. Mohan CD, Srinivasa V, Rangappa S, Mervin L, Mohan S, Paricharak S, et al. Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway. PLoS ONE. 2016;11(4):e0153155.

6. Lee JH, Chinnathambi A, Alharbi SA, Shair OHM, Sethi G, Ahn KS. Farnesol abrogates epithelial to mesenchymal transition process through regulating Akt/mTOR pathway. Pharmacol Res. 2019;150: 104504.

7. Tewari D, Patni P, Bishayee A, Sah AN. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy. Semin Cancer Biol. 2022;80:1-17.

8. Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74-88.

9. Yang MH, Lee JH, Ko JH, Jung SH, Sethi G, Ahn KS. Brassinin Represses Invasive Potential of Lung Carcinoma Cells through Deactivation of PI3K/Akt/mTOR Signaling Cascade. Molecules. 2019;24(8):1584.

10. Siveen KS, Ahn KS, Ong TH, Shanmugam MK, Li F, Yap WN, et al. Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget. 2014;5(7):1897-911.

11. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988-1004.

12. Lee JH, Kim C, Um JY, Sethi G, Ahn KS. Casticin-Induced Inhibition of Cell Growth and Survival Are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade. Cancers (Basel). 2019;11(2):254.

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17. Yuan Y, Long H, Zhou Z, Fu Y, Jiang B. PI3K-AKT-Targeting Breast Cancer Treatments: Natural Products and Synthetic Compounds. Biomolecules. 2023;13(1):93.

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25. Ashrafizadeh M, Zarrabi A, Hushmandi K, Kalantari M, Moham-adinejad R, Javaheri T, et al. Association of the Epithelial-Mesenchymal Transition (EMT) with Cisplatin Resistance. Int J Mol Sci. 2020;21(11):4002.

26. Deng J, Bai X, Feng X, Ni J, Beretov J, Graham P, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer. 2019;19(1):618.

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99. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.

100. Zhou YA, Zhang T, Zhao JB, Wang XP, Jiang T, Gu ZP, et al. The adenovirus-mediated transfer of PTEN inhibits the growth of esophageal cancer cells in vitro and in vivo. *Biosci Biotechnol Biochem. 2010;74(4):736–40.

101. Zhu W, Shao Y, Yang M, Jia M, Peng Y. Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K/AKT signaling pathway. *Gene*. 2016;594(2):176–82.

102. Lee JS, Kim HS, Kim YB, Lee MC, Park CS. Expression of PTEN in renal cell carcinoma and its relation to tumor behavior and growth. *J Surg Oncol*. 2003;84(3):166–72.

103. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. *Science*. 1997;275(5308):1943–7.

104. Hsieh SM, Maguire DJ, Lintell NA, McCabe M, Griffiths LR. PTEN and NDUFB8 aberrations in cervical cancer tissue. *Adv Exp Med Biol*. 2007;599:31–6.

105. Takei Y, Saga Y, Mizukami H, Takayama T, Ohwada M, Ozawa K, et al. Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice. *Mol Cancer Ther*. 2008;7(3):704–11.

106. Grossmann AH, Layfield LJ, Randall RL. Classification, molecular characterization, and the significance of pten alteration in leiomyosarcoma. *Sarcoma*. 2012;2012: 380896.

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108. Kim SW, Kim SM, Bae H, Nam D, Lee JH, Lee SG, et al. Embelin inhibits growth and induces apoptosis through the suppression of Akt/mTOR/S6K1 signaling cascades. *Prostate*. 2013;73(3):296–305.

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145. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-76.

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147. Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci. 2020;10(1):54.

148. Mayer IA, Arteaga CL. The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med. 2016;67:11-28.

149. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485(7396):55-61.

150. Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60(13):3504-13.

151. Shah OJ, Hunter T. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol Cell Biol. 2006;26(17):6425-34.

152. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Bran-nigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-39.

153. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PI3K3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005;11(8):2875-8.

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156. Li Z, Yang Z, Passaniti A, Lapidus RG, Liu X, Cullen KJ, et al. A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation. Oncotarget. 2016;7(22):31892-906.

157. Haddadi N, Lin Y, Travis G, Simpson AM, Nassif NT, McGowan EM. PTEN/PTENP1: "Regulating the regulator of RTK-dependent PI3K/Akt signaling", new targets for cancer therapy. Mol Cancer. 2018;17(1):37.

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159. Shafei MA, Forshaw T, Davis J, Flemban A, Qualtrough D, Dean S, et al. BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer. Onco-target. 2020;11(21):1971-87.

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163. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 2011;30(22):2547-57.

164. Fukumoto S, Hsieh CM, Maemura K, Layne MD, Yet SF, Lee KH, et al. Akt participation in the Wnt signaling pathway through Dishevelled. J Biol Chem. 2001;276(20):17479-83.

165. Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, et al. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007;282(15):11221-9.

166. Dihlmann S, Kloor M, Fallsehr C, von Knebel DM. Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells. Carcinogenesis. 2005;26(9):1503-12.

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168. Jozwiak J, Kotulska K, Grajkowska W, Jozwiak S, Zalewski W, Oldak M, et al. Upregulation of the WNT pathway in tuberous sclerosis-associated subependymal giant cell astrocytomas. Brain Dev. 2007;29(5):273-80.

169. Pecoraro C, Faggion B, Balboni B, Carbone D, Peters GJ, Diana P, et al. GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer. Drug Resist Updat. 2021;58:100779.

170. Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999;401(6748):86-90.

171. Tilton B, Andjelkovic M, Didichenko SA, Hemmings BA, Thelen M. G-Protein-coupled receptors and Fcgamma-receptors mediate activation of Akt/protein kinase B in human phagocytes. J Biol Chem. 1997;272(44):28096-101.

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173. Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 1999;19(8):5800-10.

174. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001;3(11):973-82.

175. Wijnen R, Pecoraro C, Carbone D, Fiùji H, Avan A, Peters GJ, et al. Cyclin Dependent Kinase-1 (CDK-1) Inhibition as a Novel Therapeutic Strategy against Pancreatic Ductal Adenocarcinoma (PDAC). Cancers (Basel). 2021;13(17):4389.

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133. Duda P, Akula SM, Abrams SL, Steelman LS, Martelli AM, Cocco L, et al. Targeting GSK3 and Associated Signaling Pathways Involved in Cancer. Cells. 2020;9(5):1110.

134. Chiang YJ, Liao WT, Ho KC, Wang SH, Chen YG, Ho CL, et al. CBAP modulates Akt-dependent TSC2 phosphorylation to promote Rheb-mTORC1 signaling and growth of T-cell acute lymphoblastic leukemia. Oncogene. 2019;38(9):1432-47.

135. Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul. 2017;65:5-15.

136. Davis NM, Sokolosky M, Stadelman K, Abrams SL, Libra M, Candido S, et al. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention. Oncotarget. 2014;5(13):4603-50.

137. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378(6559):785-9.

138. Stambolic V, Woodgett JR. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J. 1994;303(Pt 3):701-4.

139. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108(6):837-47.

140. Jiang Y, Yan F, Feng Z, Lazarovici P, Zheng W. Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction. Cells. 2019;9(1):100.

141. Webb AE, Brunet A. FOXO transcription factors: key regulators of cellular quality control. Trends Biochem Sci. 2014;39(4):159-69.

142. Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17(1):104.

143. Kodani N, Nakae J. Tissue-Specific Metabolic Regulation of FOXO-Binding Protein: FOXO Does Not Act Alone. Cells. 2020;9(3):702.

144. Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene. 2008;27(16):2312-9.

145. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960-76.

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147. Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci. 2020;10(1):54.

148. Mayer IA, Arteaga CL. The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med. 2016;67:11-28.

149. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485(7396):55-61.

150. Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000;60(13):3504-13.

151. Shah OJ, Hunter T. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol Cell Biol. 2006;26(17):6425-34.

152. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Bran-nigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-39.

153. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PI3K3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005;11(8):2875-8.

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155. Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 2017;552(7685):368-73.

156. Li Z, Yang Z, Passaniti A, Lapidus RG, Liu X, Cullen KJ, et al. A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation. Oncotarget. 2016;7(22):31892-906.

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158. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008;27(41):5527-41.

159. Shafei MA, Forshaw T, Davis J, Flemban A, Qualtrough D, Dean S, et al. BCAATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer. Onco-target. 2020;11(21):1971-87.

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162. Chiu H, Buono R, Jackson LV, Herzog LO, Mallya S, Conn CS, et al. Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function. iScience. 2021;24(7).

163. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 2011;30(22):2547-57.

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165. Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, et al. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007;282(15):11221-9.

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167. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006;126(5):955-68.

168. Jozwiak J, Kotulska K, Grajkowska W, Jozwiak S, Zalewski W, Oldak M, et al. Upregulation of the WNT pathway in tuberous sclerosis-associated subependymal giant cell astrocytomas. Brain Dev. 2007;29(5):273-80.

169. Pecoraro C, Faggion B, Balboni B, Carbone D, Peters GJ, Diana P, et al. GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer. Drug Resist Updat. 2021;58:100779.

170. Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999;401(6748):86-90.

171. Tilton B, Andjelkovic M, Didichenko SA, Hemmings BA, Thelen M. G-Protein-coupled receptors and Fcgamma-receptors mediate activation of Akt/protein kinase B in human phagocytes. J Biol Chem. 1997;272(44):28096-101.

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175. Wijnen R, Pecoraro C, Carbone D, Fiùji H, Avan A, Peters GJ, et al. Cyclin Dependent Kinase-1 (CDK-1) Inhibition as a Novel Therapeutic Strategy against Pancreatic Ductal Adenocarcinoma (PDAC). Cancers (Basel). 2021;13(17):4389.

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202. Liu B, Liu Y, Zhou M, Yao S, Bian Z, Liu D, et al. Comprehensive ceRNA network analysis and experimental studies identify an IGF2-AS/ miR-150/IGF2 regulatory axis in colorectal cancer. Pathol Res Pract. 2020;216(10): 153104.

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204. Zhang Y, Yan H, Jiang Y, Chen T, Ma Z, Li F, et al. Long non-coding RNA IGF2-AS represses breast cancer tumorigenesis by epigenetically regulating IGF2. Exp Biol Med (Maywood). 2021;246(4):371-9.

205. Liu R, Chen Y, Liu G, Li C, Song Y, Cao Z, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020;11(9):797.

206. Sirico M, D'Angelo A, Gianni C, Casadei C, Merloni F, De Giorgi U. Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy. Cancers (Basel). 2023;15(3):703.

207. Yu M, Chen J, Xu Z, Yang B, He Q, Luo P, et al. Development and safety of PI3K inhibitors in cancer. Arch Toxicol. 2023;97(3):635-50.

208. Hillmann P, Fabbro D. PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases. Int J Mol Sci. 2019;20(22):5792.

209. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627-44.

210. Liu N, Rowley BR, Bull CO, Schneider C, Haegebarth A, Schatz CA, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013;12(11):2319-30.

211. Markham A. Copanlisib: First Global Approval. Drugs. 2017;77(18):2057-62.

212. Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol. 2016;27(10):1928-40.

213. Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169-78.

214. Lenz G, Hawkes E, Verhoef G, Haioun C, Thye Lim S, Seog Heo D, et al. Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma. Leukemia. 2020;34(8):2184-97.

215. Dreyling M, Santoro A, Mollica L, Leppä S, Follows GA, Lenz G, et al. Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2017;35(35):3898-905.

216. Doi T, Fuse N, Yoshino T, Kojima T, Bando H, Miyamoto H, et al. A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. Cancer Chemother Pharmacol. 2017;79(1):89-98.

217. Damodaran S, Zhao F, Deming DA, Mitchell EP, Wright JJ, Gray RJ, et al. Phase II Study of Copanlisib in Patients With Tumors With PIK3CA Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F. J Clin Oncol. 2022;40(14):1552-61.

218. Qualls D, Lam HYJ, Whiting K, Kumar A, Matasar MJ, Owens C, et al. A phase 1 trial of copanlisib plus ibrutinib in relapsed/refractory mantle cell lymphoma. Blood Adv. 2022;5262-6.

219. Yhim HY, Kim T, Kim SJ, Shin HJ, Koh Y, Kim JS, et al. Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial. Ann Oncol. 2021;32(4):552-9.

220. Matasar MJ, Dreyling M, Leppä S, Santoro A, Pedersen M, Buvaylo V, et al. Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2021;21(11):e886-94.

221. Matasar MJ, Capra M, Özcan M, Lv F, Li W, Yañez E, et al. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind,
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222. Ramanathan RK, Von Hoff DD, Eskens F, Blumenschein G, Richards D, Genvresse I, et al. Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer. Target Oncol. 2020;15(2):163-74.

223. Kim RD, Alberts SR, Peña C, Genvresse I, Ajavon-Hartmann A, Xia C, et al. Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer. Br J Cancer. 2018;118(4):462-70.

224. Tan ES, Cao B, Kim J, Al-Toubah TE, Mehta R, Centeno BA, et al. Phase 2 study of copanlisib in combination with gemcitabine and cisplatin in advanced biliary tract cancers. Cancer. 2021;127(8):1293-300.

225. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550-62.

226. Narayan P, Prowell TM, Gao JJ, Fernandes LL, Li E, Jiang X, et al. FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer. Clin Cancer Res. 2021;27(7):1842-9.

227. Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. Int J Mol Sci. 2023;24(5):4522.

228. Savas P, Lo LL, Luen SJ, Blackley EF, Callahan J, Moodie K, et al. Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study. Cancer Discov. 2022;12(9):2058-73.

229. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al. Phosphatidylinositol 3-Kinase α-Selective Phosphatase Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J Clin Oncol. 2018;36(13):1291-9.

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222. Ramanathan RK, Von Hoff DD, Eskens F, Blumenschein G, Richards D, Genvresse I, et al. Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer. Target Oncol. 2020;15(2):163-74.

223. Kim RD, Alberts SR, Peña C, Genvresse I, Ajavon-Hartmann A, Xia C, et al. Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer. Br J Cancer. 2018;118(4):462-70.

224. Tan ES, Cao B, Kim J, Al-Toubah TE, Mehta R, Centeno BA, et al. Phase 2 study of copanlisib in combination with gemcitabine and cisplatin in advanced biliary tract cancers. Cancer. 2021;127(8):1293-300.

225. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550-62.

226. Narayan P, Prowell TM, Gao JJ, Fernandes LL, Li E, Jiang X, et al. FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer. Clin Cancer Res. 2021;27(7):1842-9.

227. Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. Int J Mol Sci. 2023;24(5):4522.

228. Savas P, Lo LL, Luen SJ, Blackley EF, Callahan J, Moodie K, et al. Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study. Cancer Discov. 2022;12(9):2058-73.

229. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al. Phosphatidylinositol 3-Kinase α-Selective Phosphatase Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J Clin Oncol. 2018;36(13):1291-9.

230. Ando Y, Iwasa S, Takahashi S, Saka H, Kakizume T, Natsume K, et al. Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2019;110(3):1021-31.

231. Jain S, Santa-Maria CA, Rademaker A, Giles FJ, Cristofanilli M, Gradishar WJ. Phase I study of Alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy. (Abstract). J Clin Oncol. 2017;35(15):1026.

232. Juric D, Janku F, Rodón J, Burris HA, Mayer IA, Schuler M, et al. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2019;5(2): e184475.

233. Turner S, Chia S, Kanakamedala H, Hsu WC, Park J, Chandiwana D, et al. Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. Oncologist. 2021;26(7):e1133-42.

234. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-40.

235. André F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-17.

236. Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, et al. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res. 2017;23(1):26-34.

237. Munster PM, Hamilton EP, Estevez LG, De Boer RH, Mayer, IA, et al. Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2- breast cancer. (Abstract). J Clin Oncol. 2014;32(26):143.

238. Mayer IA, Prat A, Egle D, Blau S, Fidalgo JAP, Gnant M, et al. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Clin Cancer Res. 2019;25(10):2975-87.

239. Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH, et al. Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nat Cancer. 2020;1(4):382-93.

240. Sharma P, Abramson VG, O'Dea A, Nye L, Mayer I, Pathak HB, et al. Clinical and Biomarker Results from Phase I/II Study of PI3K Inhibitor Alpelisib plus Nab-paclitaxel in HER2-Negative Metastatic Breast Cancer. Clin Cancer Res. 2021;27(14):3896-904.

241. Batalini F, Xiong N, Tayob N, Polak M, Eismann J, Cantley LC, et al. Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer. Clin Cancer Res. 2022;28(8):1493-9.

242. Jhaveri K, Drago JZ, Shah PD, Wang R, Pareja F, Ratzon F, et al. A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer. Clin Cancer Res. 2021;27(14):3867-75.

243. Pantaleo MA, Heinrich MC, Italiano A, Valverde C, Schöffski P, Grignani G, et al. A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor. BMC Cancer. 2022;22(1):511.

244. Hyman DM, Tran B, Jaime JC, Garralda E, Machiels JPH, Schellens JHM, et al. Phase Ib study of BGJ398 in combination with BYL719 in patients (pts) with select advanced solid tumors. (Abstract). J Clin Oncol. 2016;34(15):2500.

245. Juric D, Soria JC, Sharma S, Banerji U, Azaro A, Desai J, et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. (Abstract). J Clin Oncol. 2014;32(15):9051.

246. Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, et al. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019;20(4):570-80.

247. Dunn LA, Riaz N, Fury MG, McBride SM, Michel L, Lee NY, et al. A Phase 1b Study of Cetuximab and BYL719 (Alpelisib) Concurrent with Intensity Modulated Radiation Therapy in Stage III-IVB Head and Neck Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys. 2020;106(3):564-70.

248. Curigliano G, Martin M, Jhaveri K, Beck JT, Tortora G, Fazio N, et al. Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre study. Eur J Cancer. 2021;151:49-62.

249. van Geel RMJ, Tabernero J, Elez E, Bendell JC, Spreafico A, Schuler M, et al. A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic Cancer Discov. 2017;7(6):610-9.

250. Tabernero J, Van Geel R, Guren TK, Yaeger RD, Spreafico A, Faris JE, et al. Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without Alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC). (Abstract). J Clin Oncol. 2016;34(15):3544.

251. Blair HA. Duvelisib: First Global Approval. Drugs. 2018;78(17):1847-53.

252. Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, et al. Activity of the PI3K-δ, γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-98.

253. Izutsu K, Kato K, Kiyoi H, Yamamoto G, Shimada K, Akashi K. Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma. Int J Hematol. 2020;112(4):504-9.

254. Flinn IW, O'Brien S, Kahl B, Patel M, Oki Y, Foss FF, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ, γ, is clinically active in advanced hematologic malignancies. Blood. 2018;131(8):877-87.

255. Zheng Z, Gao Y, Song Y, Qian Y, Jing H, Liu T, et al. Efficacy and safety of duvelisib, a phosphoinositide 3 kinase (PI3K) δ and γ inhibitor, in Chinese patients (pts) with relapsed/refractory follicular lymphoma (R/R FL): A singlearm, open-label, multicenter, phase II clinical trial. (Abstract). J Clin Oncol. 2021;39(15):e19532.

256. Flinn IW, Miller CB, Ardeshna KM, Tetreault S, Assouline SE, Mayer J, et al. DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. J Clin Oncol. 2019;37(11):912-22.

257. Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446-55.

258. Davids MS, Kuss BJ, Hillmen P, Montillo M, Moreno C, Essell J, et al. Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study. Clin Cancer Res. 2020;26(9):2096-103.

259. Flinn IW, Cherry MA, Maris MB, Matous JV, Berdeja JG, Patel M. Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia. Am J Hematol. 2019;94(12):1325-34.
260. Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, et al. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021;35(4):1064-72.

261. Miller BW, Przepiorka D, de Claro RA, Lee K, Nie L, Simpson N, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015;21(7):1525-9.

262. Shah A, Mangaonkar A. Idelalisib: A Novel PI3Kδ Inhibitor for Chronic Lymphocytic Leukemia. Ann Pharmacother. 2015;49(10):1162-70.

263. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-7.

264. Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR, et al. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123(22):3398-405.

265. Flinn IW, Kahl BS, Leonard JP, Furman RR, Brown JR, Byrd JC, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123(22):3406-13.

266. Fukuhara N, Kinoshita T, Yamamoto K, Nagai H, Izutsu K, Yamamoto G, et al. Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia. Jpn J Clin Oncol. 2020;50(12):1395-402.

267. Gopal AK, Fanale MA, Moskowitz CH, Shustov AR, Mitra S, Ye W, et al. Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma. Ann Oncol. 2017;28(5):1057-63.

268. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-18.

269. Fjordén K, Ekberg S, Kuric N, Smedby KE, Lagerlöf I, Larsen TS, et al. Idelalisib in relapsed/refractory diffuse large B-cell lymphoma: results from a Nordic Lymphoma Group phase II trial. Br J Haematol. 2021;196(2):437-40.

270. Coutre SE, Flinn IW, de Vos S, Barrientos JC, Schreeder MT, Wagner-Johnson ND, et al. Idelalisib in Combination With Rituximab or Bendamustine or Both in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia. Hemasphere. 2018;2(3): e39.

271. O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015;126(25):2686-94.

272. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.

273. Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol. 2019;37(16):1391-402.

274. Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020;38(25):2849-61.

275. Eyre TA, Preston G, Kagdi H, Islam A, Nicholson T, Smith HW, et al. A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel). Br J Haematol. 2021;194(1):69-77.

276. Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, et al. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020;26(12):2810-8.

277. Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017;4(3):e114-26.

278. Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, et al. Idelalisib or placebo in combination with bendamustine and

rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017;18(3):297-311.

279. Tomowiak C, Poulain S, Herbaux C, Perrot A, Mahé B, Morel P, et al. Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia. Blood Adv. 2021;5(9):2438-46.

280. Dhillon S, Keam SJ. Umbralisib: First Approval. Drugs. 2021;81(7):857-66.

281. Fowler NH, Samaniego F, Jurczak W, Ghosh N, Derenzini E, Reeves JA, et al. Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2021;39(15):1609-18.

282. Chavez JC, Goldschmidt N, Samaniego F, Wrobel T, Cavallo F, Fonseca G, et al. The combination of Umbralisib plus Oblituximab is active in patients with relapsed or refractory marginal zone lymphoma (MZL): results from the phase 2 global unity-NHL trial. (Abstract). Blood. 2021;138(1):45.

283. Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020;21(3):345-57.

284. Sidaway P. Capivasertib delays disease progression. Nat Rev Clin Oncol. 2023. https://doi.org/10.1038/s41571-023-00790-x. Online ahead of print.

285. Turner N. Capivasertib Doubles PFS in Some Breast Cancers. Cancer Discov. 2023;13(2):250.

286. Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023;388(22):2058-70.

287. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-81.

288. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-101.

289. Mao B, Zhang Q, Ma L, Zhao DS, Zhao P, Yan P. Overview of Research into mTOR Inhibitors. Molecules. 2022;27(16):5295.

290. Machl A, Wilker EW, Tian H, Liu X, Schroeder P, Clark A, et al. M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier. Am J Cancer Res. 2016;6(4):806-18.

291. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317-22.

292. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-82.

293. Lau DK, Tay RY, Yeung YH, Chionh F, Mooi J, Murone C, et al. Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study. Br J Cancer. 2018;118(7):966-71.

294. Escudier B, Molinie V, Bracarda S, Maroto P, Szczylik C, Nathan P, et al. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Eur J Cancer. 2016;69:226-35.

295. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-23.

296. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADI-ANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-77.

297. Fazio N, Buzzoni R, Delle Fave G, Tesselaar ME, Wolin E, Van Cutsem E, et al. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci. 2018;109(1):174-81.

298. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-56.
260. Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, et al. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021;35(4):1064-72.

261. Miller BW, Przepiorka D, de Claro RA, Lee K, Nie L, Simpson N, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015;21(7):1525-9.

262. Shah A, Mangaonkar A. Idelalisib: A Novel PI3Kδ Inhibitor for Chronic Lymphocytic Leukemia. Ann Pharmacother. 2015;49(10):1162-70.

263. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-7.

264. Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR, et al. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123(22):3398-405.

265. Flinn IW, Kahl BS, Leonard JP, Furman RR, Brown JR, Byrd JC, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123(22):3406-13.

266. Fukuhara N, Kinoshita T, Yamamoto K, Nagai H, Izutsu K, Yamamoto G, et al. Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia. Jpn J Clin Oncol. 2020;50(12):1395-402.

267. Gopal AK, Fanale MA, Moskowitz CH, Shustov AR, Mitra S, Ye W, et al. Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma. Ann Oncol. 2017;28(5):1057-63.

268. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-18.

269. Fjordén K, Ekberg S, Kuric N, Smedby KE, Lagerlöf I, Larsen TS, et al. Idelalisib in relapsed/refractory diffuse large B-cell lymphoma: results from a Nordic Lymphoma Group phase II trial. Br J Haematol. 2021;196(2):437-40.

270. Coutre SE, Flinn IW, de Vos S, Barrientos JC, Schreeder MT, Wagner-Johnson ND, et al. Idelalisib in Combination With Rituximab or Bendamustine or Both in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia. Hemasphere. 2018;2(3): e39.

271. O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015;126(25):2686-94.

272. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.

273. Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol. 2019;37(16):1391-402.

274. Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020;38(25):2849-61.

275. Eyre TA, Preston G, Kagdi H, Islam A, Nicholson T, Smith HW, et al. A retrospective observational study to evaluate the clinical outcomes and routine management of patients with chronic lymphocytic leukaemia treated with idelalisib and rituximab in the UK and Ireland (RETRO-idel). Br J Haematol. 2021;194(1):69-77.

276. Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, et al. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020;26(12):2810-8.

277. Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017;4(3):e114-26.

278. Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, et al. Idelalisib or placebo in combination with bendamustine and

rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017;18(3):297-311.

279. Tomowiak C, Poulain S, Herbaux C, Perrot A, Mahé B, Morel P, et al. Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia. Blood Adv. 2021;5(9):2438-46.

280. Dhillon S, Keam SJ. Umbralisib: First Approval. Drugs. 2021;81(7):857-66.

281. Fowler NH, Samaniego F, Jurczak W, Ghosh N, Derenzini E, Reeves JA, et al. Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2021;39(15):1609-18.

282. Chavez JC, Goldschmidt N, Samaniego F, Wrobel T, Cavallo F, Fonseca G, et al. The combination of Umbralisib plus Oblituximab is active in patients with relapsed or refractory marginal zone lymphoma (MZL): results from the phase 2 global unity-NHL trial. (Abstract). Blood. 2021;138(1):45.

283. Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020;21(3):345-57.

284. Sidaway P. Capivasertib delays disease progression. Nat Rev Clin Oncol. 2023. https://doi.org/10.1038/s41571-023-00790-x. Online ahead of print.

285. Turner N. Capivasertib Doubles PFS in Some Breast Cancers. Cancer Discov. 2023;13(2):250.

286. Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023;388(22):2058-70.

287. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-81.

288. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-101.

289. Mao B, Zhang Q, Ma L, Zhao DS, Zhao P, Yan P. Overview of Research into mTOR Inhibitors. Molecules. 2022;27(16):5295.

290. Machl A, Wilker EW, Tian H, Liu X, Schroeder P, Clark A, et al. M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier. Am J Cancer Res. 2016;6(4):806-18.

291. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317-22.

292. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-82.

293. Lau DK, Tay RY, Yeung YH, Chionh F, Mooi J, Murone C, et al. Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study. Br J Cancer. 2018;118(7):966-71.

294. Escudier B, Molinie V, Bracarda S, Maroto P, Szczylik C, Nathan P, et al. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. Eur J Cancer. 2016;69:226-35.

295. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-23.

296. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADI-ANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-77.

297. Fazio N, Buzzoni R, Delle Fave G, Tesselaar ME, Wolin E, Van Cutsem E, et al. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci. 2018;109(1):174-81.

298. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-56.
299. Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B, et al. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. JAMA Oncol. 2018;4(10):1367-74.

300. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9.

301. Tesch H, Stoetzer O, Decker T, Kurbacher CM, Marmé F, Schneeweiss A, et al. Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial. Int J Cancer. 2019;144(4):877-85.

302. Fan Y, Sun T, Shao Z, Zhang Q, Ouyang Q, Tong Z, et al. Effectiveness of adding Everolimus to the first-line treatment of advanced breast cancer in premenopausal women who experienced disease progression while receiving selective estrogen receptor modulators: a phase 2 randomized clinical trial. JAMA Oncol. 2021;7(10):e213428.

303. Bardia A, Hurvitz SA, DeMichele A, Clark AS, Zelnak A, Yardley DA, et al. Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR. Clin Cancer Res. 2021;27(15):4177-85.

304. Schmid P, Sablin MP, Bergh J, Im SA, Lu YS, Martínez N, et al. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer. Breast Cancer Res. 2021;23(1):8.

305. Ballhausen A, Wheler JJ, Karp DD, Piha-Paul SA, Fu S, Pant S, et al. Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors. Clin Cancer Res. 2021;27(5):1247-55.

306. Toi M, Shao Z, Hurvitz S, Tseng LM, Zhang Q, Shen K, et al. Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1. Breast Cancer Res. 2017;19(1):47.

307. Bautista F, Paoletti X, Rubino J, Brard C, Rezai K, Nebchi S, et al. Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial. J Clin Oncol. 2021;39(32):3546-60.

308. Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2015;33(8):930-6.

309. Jun T, Hahn NM, Sonpavde G, Albany C, MacVicar GR, Hauke R, et al. Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma. Oncologist. 2022;27(6):432-e52.

310. Soliman PT, Westin SN, Iglesias DA, Fellman BM, Yuan Y, Zhang Q, et al. Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm. Phase II Study Clin Cancer Res. 2020;26(3):581-7.

311. Harding MW. Immunophilins, mTOR, and pharmacodynamic strategies for a targeted cancer therapy. Clin Cancer Res. 2003;9(8):2882-6.

312. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926-45.

313. Pantuck AJ, Zeng G, Belldegrun AS, Figlin RA. Pathobiology, prognosis, and targeted therapy for renal cell carcinoma: exploiting the hypoxia-induced pathway. Clin Cancer Res. 2003;9(13):4641-52.

314. Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist. 2010;15(4):428-35.

315. Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, et al. Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma. J Clin Oncol. 2016;34(15):1757-63.

316. Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387(10020):770-8.

317. Major A, Kline J, Karrison TG, Fishkin PAS, Kimball AS, Petrich AM, et al. Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas. Haematologica. 2021;107(7):1608-18.

318. Tasian SK, Silverman LB, Whitlock JA, Sposto R, Loftus JP, Schafer ES, et al. Temsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001). Haematologica. 2022;107(10):2295-303.

319. Inwards DJ, Fishkin PA, LaPlant BR, Drake MT, Kurtin PJ, Nikcevich DA, et al. Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma. Ann Oncol. 2014;25(10):2020-4.

320. Kaley TJ, Panageas KS, Pentsova EI, Mellinghoff IK, Nolan C, Gavrilovic I, et al. Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma. Ann Clin Transl Neurol. 2020;7(4):429-36.

321. Trivedi ND, Armstrong S, Wang H, Hartley M, Deeken J, Ruth He A, et al. A phase I trial of the mTOR inhibitor temsirolimus in combination with capcitabine in patients with advanced malignancies. Cancer Med. 2021;10(6):1944-54.

322. Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. J Clin Oncol. 2015;33(14):1551-6.

323. Mascarenhas L, Chi YY, Hingorani P, Anderson JR, Lyden ER, Rodeberg DA, et al. Randomized Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2019;37(31):2866-74.

324. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-93.

325. Lee BJ, Boyer JA, Burnett GL, Thottumkara AP, Tibrewal N, Wilson SL, et al. Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nat Chem Biol. 2021;17(10):1065-74.

326. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016;534(7606):272-6.

327. Lee BJ, Mallya S, Dinglasan N, Fung A, Nguyen T, Herzog LO, et al. Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia. Front Oncol. 2021;11:673213.

328. Meng D, Zhao X, Yang YC, Navickas A, Helland C, Goodarzi H, et al. A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer. Oncogene. 2023;42(28):2207-17.

329. Burnett GL, Yang YC, Aggen JB, Pitzen J, Gliedt MK, Semko CM, et al. Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors. J Med Chem. 2023;66(1):149-69.

330. Burris HA, Ulahannan SV, Haura EB, Ignatius Ou SI, Capasso A, Munster PN, et al. The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study. (Abstract). Journal of Clinical Oncology. 2022;40(16):3098.

331. Emmanouilidi A, Falasca M. Targeting PDK1 for Chemosensitization of Cancer Cells. Cancers (Basel). 2017;9(10):140.

332. Sestito S, Rapposelli S. A patent update on PDK1 inhibitors (2015-present). Expert Opin Ther Pat. 2019;29(4):271-82.

333. Marine JC, Dawson SJ, Dawson MA. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer. 2020;20(12):743-56.

334. Bertucci A, Bertucci F, Gonçalves A. Phosphoinositide 3-Kinase (PI3K) Inhibitors and Breast Cancer: An Overview of Current Achievements. Cancers (Basel). 2023;15(5):1416.

335. Belli C, Repetto M, Anand S, Porta C, Subbiah V, Curigliano G. The emerging role of PI3K inhibitors for solid tumour treatment and beyond. Br J Cancer. 2023;128(12):2150-62.

336. Raith F, O'Donovan DH, Lemos C, Politz O, Haendler B. Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment. Int J Mol Sci. 2023;24(3):2289.

337. Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2012;109(8):2718-23.

338. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500-8.

339. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell. 2012;21(2):227-39.
299. Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B, et al. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. JAMA Oncol. 2018;4(10):1367-74.

300. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9.

301. Tesch H, Stoetzer O, Decker T, Kurbacher CM, Marmé F, Schneeweiss A, et al. Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial. Int J Cancer. 2019;144(4):877-85.

302. Fan Y, Sun T, Shao Z, Zhang Q, Ouyang Q, Tong Z, et al. Effectiveness of adding Everolimus to the first-line treatment of advanced breast cancer in premenopausal women who experienced disease progression while receiving selective estrogen receptor modulators: a phase 2 randomized clinical trial. JAMA Oncol. 2021;7(10):e213428.

303. Bardia A, Hurvitz SA, DeMichele A, Clark AS, Zelnak A, Yardley DA, et al. Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR. Clin Cancer Res. 2021;27(15):4177-85.

304. Schmid P, Sablin MP, Bergh J, Im SA, Lu YS, Martínez N, et al. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer. Breast Cancer Res. 2021;23(1):8.

305. Ballhausen A, Wheler JJ, Karp DD, Piha-Paul SA, Fu S, Pant S, et al. Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors. Clin Cancer Res. 2021;27(5):1247-55.

306. Toi M, Shao Z, Hurvitz S, Tseng LM, Zhang Q, Shen K, et al. Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1. Breast Cancer Res. 2017;19(1):47.

307. Bautista F, Paoletti X, Rubino J, Brard C, Rezai K, Nebchi S, et al. Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial. J Clin Oncol. 2021;39(32):3546-60.

308. Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2015;33(8):930-6.

309. Jun T, Hahn NM, Sonpavde G, Albany C, MacVicar GR, Hauke R, et al. Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma. Oncologist. 2022;27(6):432-e52.

310. Soliman PT, Westin SN, Iglesias DA, Fellman BM, Yuan Y, Zhang Q, et al. Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm. Phase II Study Clin Cancer Res. 2020;26(3):581-7.

311. Harding MW. Immunophilins, mTOR, and pharmacodynamic strategies for a targeted cancer therapy. Clin Cancer Res. 2003;9(8):2882-6.

312. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926-45.

313. Pantuck AJ, Zeng G, Belldegrun AS, Figlin RA. Pathobiology, prognosis, and targeted therapy for renal cell carcinoma: exploiting the hypoxia-induced pathway. Clin Cancer Res. 2003;9(13):4641-52.

314. Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist. 2010;15(4):428-35.

315. Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, et al. Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma. J Clin Oncol. 2016;34(15):1757-63.

316. Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387(10020):770-8.

317. Major A, Kline J, Karrison TG, Fishkin PAS, Kimball AS, Petrich AM, et al. Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas. Haematologica. 2021;107(7):1608-18.

318. Tasian SK, Silverman LB, Whitlock JA, Sposto R, Loftus JP, Schafer ES, et al. Temsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001). Haematologica. 2022;107(10):2295-303.

319. Inwards DJ, Fishkin PA, LaPlant BR, Drake MT, Kurtin PJ, Nikcevich DA, et al. Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma. Ann Oncol. 2014;25(10):2020-4.

320. Kaley TJ, Panageas KS, Pentsova EI, Mellinghoff IK, Nolan C, Gavrilovic I, et al. Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma. Ann Clin Transl Neurol. 2020;7(4):429-36.

321. Trivedi ND, Armstrong S, Wang H, Hartley M, Deeken J, Ruth He A, et al. A phase I trial of the mTOR inhibitor temsirolimus in combination with capcitabine in patients with advanced malignancies. Cancer Med. 2021;10(6):1944-54.

322. Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. J Clin Oncol. 2015;33(14):1551-6.

323. Mascarenhas L, Chi YY, Hingorani P, Anderson JR, Lyden ER, Rodeberg DA, et al. Randomized Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2019;37(31):2866-74.

324. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-93.

325. Lee BJ, Boyer JA, Burnett GL, Thottumkara AP, Tibrewal N, Wilson SL, et al. Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth. Nat Chem Biol. 2021;17(10):1065-74.

326. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016;534(7606):272-6.

327. Lee BJ, Mallya S, Dinglasan N, Fung A, Nguyen T, Herzog LO, et al. Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia. Front Oncol. 2021;11: 673213.

328. Meng D, Zhao X, Yang YC, Navickas A, Helland C, Goodarzi H, et al. A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer. Oncogene. 2023;42(28):2207-17.

329. Burnett GL, Yang YC, Aggen JB, Pitzen J, Gliedt MK, Semko CM, et al. Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors. J Med Chem. 2023;66(1):149-69.

330. Burris HA, Ulahannan SV, Haura EB, Ignatius Ou SI, Capasso A, Munster PN, et al. The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study. (Abstract). Journal of Clinical Oncology. 2022;40(16):3098.

331. Emmanouilidi A, Falasca M. Targeting PDK1 for Chemosensitization of Cancer Cells. Cancers (Basel). 2017;9(10):140.

332. Sestito S, Rapposelli S. A patent update on PDK1 inhibitors (2015-present). Expert Opin Ther Pat. 2019;29(4):271-82.

333. Marine JC, Dawson SJ, Dawson MA. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer. 2020;20(12):743-56.

334. Bertucci A, Bertucci F, Gonçalves A. Phosphoinositide 3-Kinase (PI3K) Inhibitors and Breast Cancer: An Overview of Current Achievements. Cancers (Basel). 2023;15(5):1416.

335. Belli C, Repetto M, Anand S, Porta C, Subbiah V, Curigliano G. The emerging role of PI3K inhibitors for solid tumour treatment and beyond. Br J Cancer. 2023;128(12):2150-62.

336. Raith F, O'Donovan DH, Lemos C, Politz O, Haendler B. Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment. Int J Mol Sci. 2023;24(3):2289.

337. Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2012;109(8):2718-23.

338. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500-8.

339. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell. 2012;21(2):227-39.
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342. Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med. 2015;7(283):283ra51.

343. Scheffold A, Jebaraj BMC, Bloehdorn J, Tausch E, Bahlo J, Robrecht S, et al. High IGF1R Expression Is Associated with Worse Prognosis in CLL and Impacts Response to PI3K-δ Inhibitor Treatment. Blood. 2017;130(641):390.

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