bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Data from Cytotoxic Engineered Induced Neural Stem Cells as an Intravenous Therapy for Primary Non–Small Cell Lung Cancer and Triple-Negative Breast Cancer
Authors: Mercer-Smith Alison R. , Jiang Wulin , Bago Juli R. , Valdivia Alain , Thang Morrent , Woodell Alex S. , Montgomery Stephanie A. , Sheets Kevin T. , Anders Carey K. , Hingtgen Shawn D.
Published: April 2023

Supplementary Data containing Figures S1-S9
Supplementary Materials and Methods SM1 from Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer
Authors: Khawaja Hajrah , Briggs Rebecca , Latimer Cheryl H. , Rassel Mustasin , Griffin Daryl , Hanson Lyndsey , Bardelli Alberto , Di Nicolantonio Frederica , McDade Simon S. , Scott Christopher J. , Lambe Shauna , Maurya Manisha , Lindner Andreas U. , Prehn Jochen H.M. , Sousa Jose , Winnington Chris , LaBonte Melissa J. , Ross Sarah , Van Schaeybroeck Sandra
Published: April 2023

Supplementary materials and methods
Supplementary Figures S1-S6 from Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer
Authors: Khawaja Hajrah , Briggs Rebecca , Latimer Cheryl H. , Rassel Mustasin , Griffin Daryl , Hanson Lyndsey , Bardelli Alberto , Di Nicolantonio Frederica , McDade Simon S. , Scott Christopher J. , Lambe Shauna , Maurya Manisha , Lindner Andreas U. , Prehn Jochen H.M. , Sousa Jose , Winnington Chris , LaBonte Melissa J. , Ross Sarah , Van Schaeybroeck Sandra
Published: April 2023

Supplementary figures
Supplementary Figure from Systemic Checkpoint Blockade by PD-L1 Single-Chain Antibody Confers Potent Antitumor Immunity and Long-term Survival
Authors: Wang Hong , Khattar Vinayak , Hensel Jonathan A. , Ashton Reading , Lu Yun , Sorace Anna G. , Wang Yong , Deshane Jessy S. , Mieher Joshua L. , Deivanayagam Champion , Ponnazhagan Selvarangan
Published: April 2023

Supplementary Figure from Systemic Checkpoint Blockade by PD-L1 Single-Chain Antibody Confers Potent Antitumor Immunity and Long-term Survival
Supplementary Data from The Bispecific Tumor Antigen-Conditional 4–1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
Authors: Nelson Michelle H. , Fritzell Sara , Miller Robert , Werchau Doreen , Van Citters Danielle , Nilsson Anneli , Misher Lynda , Ljung Lill , Bader Robert , Deronic Adnan , Chunyk Allison G. , Schultz Lena , Varas Laura A. , Rose Nadia , Håkansson Maria , Gross Jane , Furebring Christina , Pavlik Peter , Sundstedt Anette , Veitonmäki Niina , Ramos Hilario J. , Säll Anna , Dahlman Anna , Bienvenue David , von Schantz Laura , McMahan Catherine J. , Askmyr Maria , Hernandez-Hoyos Gabriela , Ellmark Peter
Published: April 2023

Supplementary figures and methods
Supplementary Data from Lurbinectedin Inhibits the EWS–WT1 Transcription Factor in Desmoplastic Small Round Cell Tumor
Authors: Gedminas Jenna M. , Kaufman Rebecca , Boguslawski Elissa A. , Gross Amy C. , Adams Marie , Beddows Ian , Kitchen-Goosen Susan M. , Roberts Ryan D. , Grohar Patrick J.
Published: April 2023

Supplementary Data from Lurbinectedin Inhibits the EWS–WT1 Transcription Factor in Desmoplastic Small Round Cell Tumor
Figure S5 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death
Authors: Jenkins Laura J. , Luk Ian Y. , Fairlie W. Douglas , Lee Erinna F. , Palmieri Michelle , Schoffer Kael L. , Tan Tao , Ng Irvin , Vukelic Natalia , Tran Sharon , Tse Janson W.T. , Nightingale Rebecca , Alam Zakia , Chionh Fiona , Iatropoulos George , Ernst Matthias , Afshar-Sterle Shoukat , Desai Jayesh , Gibbs Peter , Sieber Oliver M. , Dhillon Amardeep S. , Tebbutt Niall C. , Mariadason John M.
Published: April 2023

Supplementary figure 5 shows mouse weight during treatment in two of the mouse studies
Supplementary Figure from Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy
Authors: Sinnett-Smith James , Anwar Tarique , Reed Elaine F. , Teper Yaroslav , Eibl Guido , Rozengurt Enrique
Published: April 2023

Supplementary Figure from Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy
Figure S4 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death
Authors: Jenkins Laura J. , Luk Ian Y. , Fairlie W. Douglas , Lee Erinna F. , Palmieri Michelle , Schoffer Kael L. , Tan Tao , Ng Irvin , Vukelic Natalia , Tran Sharon , Tse Janson W.T. , Nightingale Rebecca , Alam Zakia , Chionh Fiona , Iatropoulos George , Ernst Matthias , Afshar-Sterle Shoukat , Desai Jayesh , Gibbs Peter , Sieber Oliver M. , Dhillon Amardeep S. , Tebbutt Niall C. , Mariadason John M.
Published: April 2023

Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse
Figure S2 from Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death
Authors: Jenkins Laura J. , Luk Ian Y. , Fairlie W. Douglas , Lee Erinna F. , Palmieri Michelle , Schoffer Kael L. , Tan Tao , Ng Irvin , Vukelic Natalia , Tran Sharon , Tse Janson W.T. , Nightingale Rebecca , Alam Zakia , Chionh Fiona , Iatropoulos George , Ernst Matthias , Afshar-Sterle Shoukat , Desai Jayesh , Gibbs Peter , Sieber Oliver M. , Dhillon Amardeep S. , Tebbutt Niall C. , Mariadason John M.
Published: April 2023

Supplementary figure 2 shows the effect of trametinib plus panobinostat on colony formation in HCT 116 cells
Supplementary Figure 1 from Inhibition of the MNK1/2–eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer
Authors: Prabhu Sathyen A. , Moussa Omar , Gonçalves Christophe , LaPierre Judith H. , Chou Hsiang , Huang Fan , Richard Vincent R. , Ferruzo Pault Y. M. , Guettler Elizabeth M. , Soria-Bretones Isabel , Kirby Laura , Gagnon Natascha , Su Jie , Silvester Jennifer , Krisna Sai Sakktee , Rose April A. N. , Sheppard Karen E. , Cescon David W. , Mallette Frédérick A. , Zahedi Rene P. , Borchers Christoph H. , del Rincon Sonia V. , Miller Wilson H.
Published: April 2023

Supplementary Figure 1
Supplementary Data from Inhibition of the MNK1/2–eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer
Authors: Prabhu Sathyen A. , Moussa Omar , Gonçalves Christophe , LaPierre Judith H. , Chou Hsiang , Huang Fan , Richard Vincent R. , Ferruzo Pault Y. M. , Guettler Elizabeth M. , Soria-Bretones Isabel , Kirby Laura , Gagnon Natascha , Su Jie , Silvester Jennifer , Krisna Sai Sakktee , Rose April A. N. , Sheppard Karen E. , Cescon David W. , Mallette Frédérick A. , Zahedi Rene P. , Borchers Christoph H. , del Rincon Sonia V. , Miller Wilson H.
Published: April 2023

List of differentially expressed proteins annotated by cluster with pathway analysis in BLM cells
Data from Next Generation Sequencing of Prostate Cancer from a Patient Identifies a Deficiency of Methylthioadenosine Phosphorylase, an Exploitable Tumor Target
Authors: Collins Colin C. , Volik Stanislav V. , Lapuk Anna V. , Wang Yuwei , Gout Peter W. , Wu Chunxiao , Xue Hui , Cheng Hongwei , Haegert Anne , Bell Robert H. , Brahmbhatt Sonal , Anderson Shawn , Fazli Ladan , Hurtado-Coll Antonio , Rubin Mark A. , Demichelis Francesca , Beltran Himisha , Hirst Martin , Marra Marco , Maher Christopher A. , Chinnaiyan Arul M. , Gleave Martin , Bertino Joseph R. , Lubin Martin , Wang Yuzhuo
Published: April 2023

Abstract
Castrate-resistant prostate cancer (CRPC) and neuroendocrine carcinoma of the prostate are invariably fatal diseases for which only palliative therapies exist. As part of a prostate tumor sequencing program, a patient tumor was analyzed using Illumina genome sequencing and a matched renal capsule tumor xenograft was generated. Both tumor and xenograft had a homozygous 9p21 deletion spanning the MTAP, CDKN2, and ARF genes. It is rare for this deletion to occur in primary prostate tumors, yet approximately 10% express decreased levels of methylthioadenosine phosphorylase (MTAP) mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it seems that this deletion is more common in CRPC than in primary prostate cancer. We show for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient-derived neuroendocrine xenograft growth while protecting the host from 6-thioguanine toxicity. This therapeutic approach can be applied to other MTAP-deficient human cancers as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology. Mol Cancer Ther; 11(3); 775–83. ©2012 AACR.
Data from Proteasome Inhibition Blocks NF-κB and ERK1/2 Pathways, Restores Antigen Expression, and Sensitizes Resistant Human Melanoma to TCR-Engineered CTLs
Authors: Jazirehi Ali R. , Economou James S.
Published: April 2023

Abstract
Adoptive cell transfer (ACT) of ex vivo engineered autologous lymphocytes encoding high-affinity MART-1/HLA-A*0201–specific T-cell receptor (TCR)α/β chains (F5 CTL), densely infiltrate into sites of metastatic disease, mediating dramatic but partial clinical responses in patients with melanoma. We hypothesized that MART-1 downmodulation in addition to aberrant apoptotic/survival signaling could confer resistance to death signals delivered by transgenic CTLs. To explore this hypothesis, we established an in vitro model of resistant (R) lines from MART-1+/HLA-A*0201+ F5 CTL–sensitive parental (P) lines under serial F5 CTL–selective pressure. We have recently reported that several melanoma R lines, while retaining MART-1 expression, exhibited constitutive NF-κB activation and overexpression of NF-κB–dependent resistance factors. Another established melanoma cell line M244, otherwise sensitive to F5 CTL, yielded R lines after serial F5 CTL–selective pressure, which had both reduced MART-1 expression levels, thus, could not be recognized, and were resistant to CTL-delivered apoptotic death signals. The proteasome inhibitor bortezomib blocked NF-κB activity, decreased phospho-ERK1/2, increased phospho-c-jun–NH2–kinase (p-JNK) levels, reduced expression of resistance factors, restored MART-1 expression to sufficient levels, which in combination allowed M244R lines be sensitized to F5 CTL killing. These findings suggest that proteasome inhibition in immune resistant tumors can restore proapoptotic signaling and improve tumor antigen expression. Mol Cancer Ther; 11(6); 1332–41. ©2012 AACR.
Data from The Multitargeted Receptor Tyrosine Kinase Inhibitor Linifanib (ABT-869) Induces Apoptosis through an Akt and Glycogen Synthase Kinase 3β–Dependent Pathway
Authors: Hernandez-Davies Jenny E. , Zape Joan P. , Landaw Elliot M. , Tan Xiaolin , Presnell Ajia , Griffith Diana , Heinrich Michael C. , Glaser Keith B. , Sakamoto Kathleen M.
Published: April 2023

Abstract
The FMS-like receptor tyrosine kinase 3 (FLT3) plays an important role in controlling differentiation and proliferation of hematopoietic cells. Activating mutations in FLT3 occur in patients with acute myeloid leukemia (AML; 15%–35%), resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with AML harboring the FLT3 internal tandem duplication (ITD) mutation have a poor prognosis. Several inhibitors have been developed to target mutant FLT3 for the treatment of AML, yet the molecular pathways affected by drug inhibition of the mutated FLT3 receptor alone have not been characterized as yet. Linifanib (ABT-869) is a multitargeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this article, we show that treatment with linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo. We show that treatment with linifanib reduces phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β). In addition, we show that inhibition of GSK3β decreases linifanib-induced apoptosis. This study shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations. Mol Cancer Ther; 10(6); 949–59. ©2011 AACR.
Data from Ridaforolimus (AP23573; MK-8669), a Potent mTOR Inhibitor, Has Broad Antitumor Activity and Can Be Optimally Administered Using Intermittent Dosing Regimens
Authors: Rivera Victor M. , Squillace Rachel M. , Miller David , Berk Lori , Wardwell Scott D. , Ning Yaoyu , Pollock Roy , Narasimhan Narayana I. , Iuliucci John D. , Wang Frank , Clackson Tim
Published: April 2023

Abstract
The mTOR pathway is hyperactivated through oncogenic transformation in many human malignancies. Ridaforolimus (AP23573; MK-8669) is a novel rapamycin analogue that selectively targets mTOR and is currently under clinical evaluation. In this study, we investigated the mechanistic basis for the antitumor activity of ridaforolimus in a range of human tumor types, exploring potential markers of response, and determining optimal dosing regimens to guide clinical studies. Administration of ridaforolimus to tumor cells in vitro elicited dose-dependent inhibition of mTOR activity with concomitant effects on cell growth and division. We showed that ridaforolimus exhibits a predominantly cytostatic mode of action, consistent with the findings for other mTOR inhibitors. Potent inhibitory effects on vascular endothelial growth factor secretion, endothelial cell growth, and glucose metabolism were also observed. Although PTEN and/or phosphorylated AKT status have been proposed as potential mTOR pathway biomarkers, neither was predictive for ridaforolimus responsiveness in the heterogeneous panel of cancer cell lines examined. In mouse models, robust antitumor activity was observed in human tumor xenografts using a series of intermittent dosing schedules, consistent with pharmacodynamic observations of mTOR pathway inhibition for at least 72 hours following dosing. Parallel skin-graft rejection studies established that intermittent dosing schedules lack the immunosuppressive effects seen with daily dosing. Overall these findings show the broad inhibitory effects of ridaforolimus on cell growth, division, metabolism, and angiogenesis, and support the use of intermittent dosing as a means to optimize antitumor activity while minimizing systemic effects. Mol Cancer Ther; 10(6); 1059–71. ©2011 AACR.
Data from Transformation-Dependent Silencing of Tumor-Selective Apoptosis-Inducing TRAIL by DNA Hypermethylation Is Antagonized by Decitabine
Authors: Lund Per , Kotova Irina , Kedinger Valérie , Khanwalkar Harshal , Voltz Emilie , Hahn William C. , Gronemeyer Hinrich
Published: April 2023

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) kills tumor cells selectively. We asked how emerging tumor cells escape elimination by TRAIL and how tumor-specific killing by TRAIL could then be restored. We found that TRAIL expression is consistently downregulated in HRASG12V-transformed cells in stepwise tumorigenesis models derived from four different tissues due to DNA hypermethylation of CpG clusters within the TRAIL promoter. Decitabine de-silenced TRAIL, which remained inducible by interferon, while induction of TRAIL by blocking the HRASG12V-activated mitogen-activated protein kinase pathway was subordinated to epigenetic silencing. Decitabine induced apoptosis through upregulation of endogenous TRAIL in cooperation with favorable regulation of key players acting in TRAIL-mediated apoptosis. Apoptosis induction by exogenously added TRAIL was largely increased by decitabine. In vivo treatment of xenografted human HRASG12V-transformed human epithelial kidney or syngenic mice tumors by decitabine blocked tumor growth induced TRAIL expression and apoptosis. Our results emphasize the potential of decitabine to enhance TRAIL-induced apoptosis in tumors and thus provide a rationale for combination therapies with decitabine to increase tumor-selective apoptosis. Mol Cancer Ther; 10(9); 1611–23. ©2011 AACR.
Data from CBP501-Calmodulin Binding Contributes to Sensitizing Tumor Cells to Cisplatin and Bleomycin
Authors: Mine Naoki , Yamamoto Sayaka , Saito Naoya , Yamazaki Satoshi , Suda Chikako , Ishigaki Machiyo , Kufe Donald W. , Von Hoff Daniel D. , Kawabe Takumi
Published: April 2023

Abstract
CBP501 is an anticancer drug currently in randomized phase II clinical trials for patients with non–small cell lung cancer and malignant pleural mesothelioma. CBP501 was originally described as a unique G2 checkpoint-directed agent that binds to 14-3-3, inhibiting the actions of Chk1, Chk2, mitogen-activated protein kinase-activated protein kinase 2, and C-Tak1. However, unlike a G2 checkpoint inhibitor, CBP501 clearly enhances the accumulation of tumor cells at G2–M phase that is induced by cisplatin or bleomycin at low doses and short exposure. By contrast, CBP501 does not similarly affect the accumulation of tumor cells at G2–M that is induced by radiation, doxorubicin, or 5-fluorouracil treatment. Our recent findings point to an additional mechanism of action for CBP501. The enhanced accumulation of tumor cells at G2–M upon combined treatment with cisplatin and CBP501 results from an increase in intracellular platinum concentrations, which leads to increased binding of platinum to DNA. The observed CBP501-enhanced platinum accumulation is negated in the presence of excess Ca2+. Some calmodulin inhibitors behave similarly to, although less potently than, CBP501. Furthermore, analysis by surface plasmon resonance reveals a direct, high-affinity molecular interaction between CBP501 and CaM (Kd = 4.62 × 10−8 mol/L) that is reversed by Ca2+, whereas the Kd for the complex between CBP501 and 14-3-3 is approximately 10-fold weaker and is Ca2+ independent. We conclude that CaM inhibition contributes to CBP501′s activity in sensitizing cancer cells to cisplatin or bleomycin. This article presents an additional mechanism of action which might explain the clinical activity of the CBP501–cisplatin combination. Mol Cancer Ther; 10(10); 1929–38. ©2011 AACR.
Data from Long Pentraxin-3 Inhibits FGF8b-Dependent Angiogenesis and Growth of Steroid Hormone–Regulated Tumors
Authors: Leali Daria , Alessi Patrizia , Coltrini Daniela , Ronca Roberto , Corsini Michela , Nardo Giorgia , Indraccolo Stefano , Presta Marco
Published: April 2023

Abstract
Fibroblast growth factor-8b (FGF8b) exerts nonredundant autocrine/paracrine functions in steroid hormone–regulated tumors. Previous observations had shown that the soluble pattern recognition receptor long pentraxin-3 (PTX3) is a natural selective antagonist for a restricted number of FGF family members, inhibiting FGF2 but not FGF1 and FGF4 activity. Here, we assessed the capacity of PTX3 to antagonize FGF8b and to inhibit the vascularization and growth of steroid hormone–regulated tumors. Surface plasmon resonance analysis shows that PTX3 binds FGF8b with high affinity (Kd = 30–90 nmol/L). As a consequence, PTX3 prevents the binding of FGF8b to its receptors, inhibits FGF8b-driven ERK1/2 activation, cell proliferation, and chemotaxis in endothelial cells, and suppresses FGF8b-induced neovascularization in vivo. Also, PTX3 inhibits dihydrotestosterone (DHT)- and FGF8b-driven proliferation of androgen-regulated Shionogi 115 (S115) mouse breast tumor cells. Furthermore, DHT-treated, PTX3 overexpressing hPTX3_S115 cell transfectants show a reduced proliferation rate in vitro and a limited angiogenic activity in the chick embryo chorioallantoic membrane and murine s.c. Matrigel plug assays. Accordingly, hPTX3_S115 cells show a dramatic decrease of their tumorigenic activity when grafted in immunodeficient male mice. These results identify PTX3 as a novel FGF8b antagonist endowed with antiangiogenic and antineoplastic activity with possible implications for the therapy of hormonal tumors. Mol Cancer Ther; 10(9); 1600–10. ©2011 AACR.
Data from Tasisulam Sodium, an Antitumor Agent That Inhibits Mitotic Progression and Induces Vascular Normalization
Authors: Meier Timothy , Uhlik Mark , Chintharlapalli Sudhakar , Dowless Michele , Van Horn Robert , Stewart Julie , Blosser Wayne , Cook James , Young Debra , Ye Xiang , Evans Glenn , Credille Kelly , Ballard Darryl , Huber Lysiane , Capen Andrew , Chedid Marcio , Ilaria Robert , Smith Michele C. , Stancato Louis
Published: April 2023

Abstract
LY573636-sodium (tasisulam) is a small molecule antitumor agent with a novel mechanism of action currently being investigated in a variety of human cancers. In vitro, tasisulam induced apoptosis via the intrinsic pathway, resulting in cytochrome c release and caspase-dependent cell death. Using high content cellular imaging and subpopulation analysis of a wide range of in vitro and in vivo cancer models, tasisulam increased the proportion of cells with 4N DNA content and phospho-histone H3 expression, leading to G2–M accumulation and subsequent apoptosis. Tasisulam also blocked VEGF, epidermal growth factor, and fibroblast growth factor–induced endothelial cell cord formation but did not block acute growth factor receptor signaling (unlike sunitinib, which blocks VEGF-driven angiogenesis at the receptor kinase level) or induce apoptosis in primary endothelial cells. Importantly, in vivo phenocopying of in vitro effects were observed in multiple human tumor xenografts. Tasisulam was as effective as sunitinib at inhibiting neovascularization in a Matrigel plug angiogenesis assay in vivo and also caused reversible, non G2–M–dependent growth arrest in primary endothelial cells. Tasisulam also induced vascular normalization in vivo. Interestingly, the combination of tasisulam and sunitinib significantly delayed growth of the Caki-1 renal cell carcinoma model, whereas neither agent was active alone. These data show that tasisulam has a unique, dual-faceted mechanism of action involving mitotic catastrophe and antiangiogenesis, a phenotype distinct from conventional chemotherapies and published anticancer agents. Mol Cancer Ther; 10(11); 2168–78. ©2011 AACR.
Data from Liposomal Delivery of MicroRNA-7–Expressing Plasmid Overcomes Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistance in Lung Cancer Cells
Authors: Rai Kammei , Takigawa Nagio , Ito Sachio , Kashihara Hiromi , Ichihara Eiki , Yasuda Tatsuji , Shimizu Kenji , Tanimoto Mitsune , Kiura Katsuyuki
Published: April 2023

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR-7), targeting multiple sites in the 3′-untranslated region of EGFR mRNA. Two EGFR-TKI–sensitive cell lines (PC-9 and H3255) and two EGFR-TKI–resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7–expressing plasmid. After transfection of the miR-7–expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR-7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC-9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7–expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7–expressing plasmids against EGFR oncogene–addicted lung cancers including T790M resistance by liposomal delivery. Mol Cancer Ther; 10(9); 1720–7. ©2011 AACR.
Data from Potent, Selective Inhibitors of Fibroblast Growth Factor Receptor Define Fibroblast Growth Factor Dependence in Preclinical Cancer Models
Authors: Squires Matthew , Ward George , Saxty Gordan , Berdini Valerio , Cleasby Anne , King Peter , Angibaud Patrick , Perera Tim , Fazal Lynsey , Ross Douglas , Jones Charlotte Griffiths , Madin Andrew , Benning Rajdeep K. , Vickerstaffe Emma , O'Brien Alistair , Frederickson Martyn , Reader Michael , Hamlett Christopher , Batey Michael A. , Rich Sharna , Carr Maria , Miller Darcey , Feltell Ruth , Thiru Abarna , Bethell Susanne , Devine Lindsay A. , Graham Brent L. , Pike Andrew , Cosme Jose , Lewis Edward J. , Freyne Eddy , Lyons John , Irving Julie , Murray Christopher , Newell David R. , Thompson Neil T.
Published: April 2023

Abstract
We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role. Mol Cancer Ther; 10(9); 1542–52. ©2011 AACR.
Data from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma
Authors: Piguet Anne-Christine , Saar Bettina , Hlushchuk Ruslan , St-Pierre Marie V. , McSheehy Paul M.J. , Radojevic Vesna , Afthinos Maresa , Terracciano Luigi , Djonov Valentin , Dufour Jean-François
Published: April 2023

Abstract
Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib. Mol Cancer Ther; 10(6); 1007–17. ©2011 AACR.
Data from Functional Analysis of the p53 Pathway in Neuroblastoma Cells Using the Small-Molecule MDM2 Antagonist Nutlin-3
Authors: Van Maerken Tom , Rihani Ali , Dreidax Daniel , De Clercq Sarah , Yigit Nurten , Marine Jean-Christophe , Westermann Frank , De Paepe Anne , Vandesompele Jo , Speleman Frank
Published: April 2023

Abstract
Suppression of p53 activity is essential for proliferation and survival of tumor cells. A direct p53-activating compound, nutlin-3, was used in this study, together with p53 mutation analysis, to characterize p53 pathway defects in a set of 34 human neuroblastoma cell lines. We identified 9 cell lines (26%) with a p53 loss-of-function mutation, including 6 missense mutations, 1 nonsense mutation, 1 in-frame deletion, and 1 homozygous deletion of the 3′ end of the p53 gene. Sensitivity to nutlin-3 was highly predictive of absence of p53 mutation. Signaling pathways downstream of p53 were functionally intact in 23 of 25 cell lines with wild-type p53. Knockdown and overexpression experiments revealed a potentiating effect of p14ARF expression on the response of neuroblastoma cells to nutlin-3. Our findings shed light on the spectrum of p53 pathway lesions in neuroblastoma cells, indicate that defects in effector molecules downstream of p53 are remarkably rare in neuroblastoma, and identify p14ARF as a determinant of the outcome of the response to MDM2 inhibition. These insights may prove useful for the clinical translation of evolving strategies aimed at p53 reactivation and for the development of new therapeutic approaches. Mol Cancer Ther; 10(6); 983–93. ©2011 AACR.
Data from Discovery of a Small Molecule Targeting IRA2 Deletion in Budding Yeast and Neurofibromin Loss in Malignant Peripheral Nerve Sheath Tumor Cells
Authors: Wood Matthew , Rawe Melissa , Johansson Gunnar , Pang Shu , Soderquist Ryan S. , Patel Ami V. , Nelson Sandra , Seibel William , Ratner Nancy , Sanchez Yolanda
Published: April 2023

Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1+/+ and NF1−/− MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Δ). Here, we describe UC1, a small molecule that targets NF1−/− cell lines and ira2Δ budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation. Mol Cancer Ther; 10(9); 1740–50. ©2011 AACR.
Data from Antisense Inhibition of Survivin Expression as a Cancer Therapeutic
Authors: Carrasco Rosa A. , Stamm Nancy B. , Marcusson Eric , Sandusky George , Iversen Philip , Patel Bharvin K.R.
Published: April 2023

Abstract
Survivin, a family member of the inhibitor of apoptosis proteins that is expressed during mitosis in a cell cycle–dependent manner and localized to different components of the mitotic apparatus, plays an important role in both cell division and inhibition of apoptosis. Survivin is expressed in a vast majority of human cancers, but not in normal adult tissues. Survivin expression is often correlated with poor prognosis in a wide variety of cancer patients. These features make survivin an attractive target against which cancer therapeutics could be developed. We have identified a survivin antisense oligonucleotide (ASO) that potently downregulated survivin expression in human cancer cells derived from lung, colon, pancreas, liver, breast, prostate, ovary, cervix, skin, and brain as measured by quantitative RT-PCR and immunoblotting analysis. Specific inhibition of survivin expression in multiple cancer cell lines by this ASO (LY2181308) induced caspase-3–dependent apoptosis, cell cycle arrest in the G2‐M phase, and multinucleated cells. We also showed that inhibition of survivin expression by LY2181308 sensitized tumor cells to chemotherapeutic-induced apoptosis. Most importantly, in an in vivo human xenograft tumor model, LY2181308 produced significant antitumor activity as compared with saline or its sequence-specific control oligonucleotide and sensitized to gemcitabine, paclitaxel, and docetaxel. Furthermore, we showed that this antitumor activity was associated with significant inhibition of survivin expression in these xenograft tumors. On the basis of these, LY2181308 is being evaluated in a clinical setting (Phase II) in combination with docetaxel for the treatment of prostate cancer. Mol Cancer Ther; 10(2); 221–32. ©2011 AACR.
Data from Spectrum of Cellular Responses to Pyriplatin, a Monofunctional Cationic Antineoplastic Platinum(II) Compound, in Human Cancer Cells
Authors: Lovejoy Katherine S. , Serova Maria , Bieche Ivan , Emami Shahin , D'Incalci Maurizio , Broggini Massimo , Erba Eugenio , Gespach Christian , Cvitkovic Esteban , Faivre Sandrine , Raymond Eric , Lippard Stephen J.
Published: April 2023

Abstract
Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum–DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC50 = 171–443 μmol/L), with maximum cytotoxicity in HOP-62 non–small cell lung cancer cells after 72 hours (IC50 = 24 μmol/L). Pyriplatin caused a G2-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin–DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use. Mol Cancer Ther; 10(9); 1709–19. ©2011 AACR.
Data from Carfilzomib Interacts Synergistically with Histone Deacetylase Inhibitors in Mantle Cell Lymphoma Cells In Vitro and In Vivo
Authors: Dasmahapatra Girija , Lembersky Dmitry , Son Minkyeong P. , Attkisson Elisa , Dent Paul , Fisher Richard I. , Friedberg Jonathan W. , Grant Steven
Published: April 2023

Abstract
Interactions between the proteasome inhibitor carfilzomib and the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275 were examined in mantle cell lymphoma (MCL) cells in vitro and in vivo. Coadministration of very low, marginally toxic carfilzomib concentrations (e.g., 3–4 nmol/L) with minimally lethal vorinostat or SNDX-275 concentrations induced sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Enhanced lethality was associated with c-jun-NH,-kinase (JNK) 1/2 activation, increased DNA damage (induction of λH2A.X), and ERK1/2 and AKT1/2 inactivation. Coadministration of carfilzomib and histone deacetylase inhibitors (HDACI) induced a marked increase in reactive oxygen species (ROS) generation and G2–M arrest. Significantly, the free radical scavenger tetrakis(4-benzoic acid) porphyrin (TBAP) blocked carfilzomib/HDACI-mediated ROS generation, λH2A.X formation, JNK1/2 activation, and lethality. Genetic (short hairpin RNA) knockdown of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, carfilzomib/vorinostat coadministration resulted in a pronounced reduction in tumor growth compared with single agent treatment in an MCL xenograft model associated with enhanced apoptosis, λH2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrant attention in MCL. Mol Cancer Ther; 10(9); 1686–97. ©2011 AACR.
Data from Drug Resistance to Inhibitors of the Human Double Minute-2 E3 Ligase Is Mediated by Point Mutations of p53, but Can Be Overcome with the p53 Targeting Agent RITA
Authors: Jones Richard J. , Bjorklund Chad C. , Baladandayuthapani Veerabhadran , Kuhn Deborah J. , Orlowski Robert Z.
Published: April 2023

Abstract
The human double minute (HDM)-2 E3 ubiquitin ligase plays a key role in p53 turnover and has been validated preclinically as a target in multiple myeloma (MM) and mantle cell lymphoma (MCL). HDM-2 inhibitors are entering clinical trials, and we therefore sought to understand potential mechanisms of resistance in lymphoid models. Wild-type p53 H929 MM and Granta-519 MCL cells resistant to MI-63 or Nutlin were generated by exposing them to increasing drug concentrations. MI-63-resistant H929 and Granta-519 cells were resistant to Nutlin, whereas Nutlin-resistant cells displayed cross-resistance to MI-63. These cells also showed cross-resistance to bortezomib, doxorubicin, cisplatin, and melphalan, but remained sensitive to the small molecule inhibitor RITA (reactivation of p53 and induction of tumor cell apoptosis). HDM-2 inhibitor-resistant cells harbored increased p53 levels, but neither genotoxic nor nongenotoxic approaches to activate p53 induced HDM-2 or p21. Resequencing revealed wild-type HDM-2, but mutations were found in the p53 DNA binding and dimerization domains. In resistant cells, RITA induced a G2–M arrest, upregulation of p53 targets HDM-2, PUMA, and NOXA, and PARP cleavage. Combination regimens with RITA and MI-63 resulted in enhanced cell death compared with RITA alone. These findings support the possibility that p53 mutation could be a primary mechanism of acquired resistance to HDM-2 inhibitors in MCL and MM. Furthermore, they suggest that simultaneous restoration of p53 function and HDM-2 inhibition is a rational strategy for clinical translation. Mol Cancer Ther; 11(10); 2243–53. ©2012 AACR.
Data from Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo
Authors: Thomas Christian , Zoubeidi Amina , Kuruma Hidetoshi , Fazli Ladan , Lamoureux Francois , Beraldi Eliana , Monia Brett P. , MacLeod A. Robert , Thüroff Joachim W. , Gleave Martin E.
Published: April 2023

Abstract
Signal transducer and activator of transcription 5 (Stat5) plays an important role in the transition of prostate cancer (PCa) to its castrate-resistant state. Pharmacologic targeting of Stat5 is a rational approach to delay castrate-resistant progression, in part, because Stat5 cooperates with the androgen receptor (AR) to promote PCa progression. Immunostaining of tissue microarrays was used to correlate Stat5 expression with Gleason grade and to characterize changes in treatment-naive and androgen-deprived human PCa. Potency of a Stat5 antisense oligonucleotide (ASO) on Stat5 knockdown, cell growth, and apoptosis was assessed in LNCaP, C4-2, and DU145 cells. Effects of Stat5 knockdown on AR activity and stability was assessed using a PSA transactivation-luciferase assay and cyclohexamide plus MG132 treatment, respectively. LNCaP tumor-bearing mice were castrated and randomly assigned to treatment with Stat5-ASO or controls. Here, we show that the frequency of Stat5 expression is significantly increased in high Gleason grade as well as in hormone-treated PCa. Also, specific knockdown of Stat5 with ASO abrogates androgen-induced AR nuclear translocation and PSA transactivation despite R1881 stimulation. Moreover, Stat5 knockdown destabilizes AR, which leads to AR degradation via the proteasome. Shown for the first time as a preclinical proof-of-principle, Stat5 knockdown with Stat5-ASO significantly delays CRPC tumor progression in vivo. Thereby, we are able to recapitulate our in vitro results by reducing serum PSA and expression levels of target proteins in the xenograft tumors. Mol Cancer Ther; 10(2); 347–59. ©2011 AACR.
Data from Comprehensive Predictive Biomarker Analysis for MEK Inhibitor GSK1120212
Authors: Jing Junping , Greshock Joel , Holbrook Joanna Dawn , Gilmartin Aidan , Zhang Xiping , McNeil Elizabeth , Conway Theresa , Moy Christopher , Laquerre Sylvie , Bachman Kurt , Wooster Richard , Degenhardt Yan
Published: April 2023

Abstract
The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors. Mol Cancer Ther; 11(3); 720–9. ©2011 AACR.
Data from GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
Authors: Wallin Jeffrey J. , Edgar Kyle A. , Guan Jane , Berry Megan , Prior Wei Wei , Lee Leslie , Lesnick John D. , Lewis Cristina , Nonomiya Jim , Pang Jodie , Salphati Laurent , Olivero Alan G. , Sutherlin Daniel P. , O'Brien Carol , Spoerke Jill M. , Patel Sonal , Lensun Letitia , Kassees Robert , Ross Leanne , Lackner Mark R. , Sampath Deepak , Belvin Marcia , Friedman Lori S.
Published: April 2023

Abstract
Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426–36. ©2011 AACR.
Data from Active Efflux of Dasatinib from the Brain Limits Efficacy against Murine Glioblastoma: Broad Implications for the Clinical Use of Molecularly Targeted Agents
Authors: Agarwal Sagar , Mittapalli Rajendar K. , Zellmer David M. , Gallardo Jose L. , Donelson Randy , Seiler Charlie , Decker Stacy A. , SantaCruz Karen S. , Pokorny Jenny L. , Sarkaria Jann N. , Elmquist William F. , Ohlfest John R.
Published: April 2023

Abstract
The importance of the blood–brain barrier in preventing effective pharmacotherapy of glioblastoma has been controversial. The controversy stems from the fact that vascular endothelial cell tight junctions are disrupted in the tumor, allowing some systemic drug delivery. P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) efflux drugs from brain capillary endothelial cells into the blood. We tested the hypothesis that although the tight junctions are “leaky” in the core of glioblastomas, active efflux limits drug delivery to tumor-infiltrated normal brain and consequently, treatment efficacy. Malignant gliomas were induced by oncogene transfer into wild-type (WT) mice or mice deficient for Pgp and BCRP (knockout, KO). Glioma-bearing mice were orally dosed with dasatinib, a kinase inhibitor and dual BCRP/PgP substrate that is being currently tested in clinical trials. KO mice treated with dasatinib survived for twice as long as WT mice. Microdissection of the tumor core, invasive rim, and normal brain revealed 2- to 3-fold enhancement in dasatinib brain concentrations in KO mice relative to WT. Analysis of signaling showed that poor drug delivery correlated with the lack of inhibition of a dasatinib target, especially in normal brain. A majority of human glioma xenograft lines tested expressed BCRP or PgP and were sensitized to dasatinib by a dual BCRP/Pgp inhibitor, illustrating a second barrier to drug delivery intrinsic to the tumor itself. These data show that active efflux is a relevant obstacle to treating glioblastoma and provide a plausible mechanistic basis for the clinical failure of numerous drugs that are BCRP/Pgp substrates. Mol Cancer Ther; 11(10); 2183–92. ©2012 AACR.