bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy
Authors: DeNardo David G. , Brennan Donal J. , Rexhepaj Elton , Ruffell Brian , Shiao Stephen L. , Madden Stephen F. , Gallagher William M. , Wadhwani Nikhil , Keil Scott D. , Junaid Sharfaa A. , Rugo Hope S. , Hwang E. Shelley , Jirström Karin , West Brian L. , Coussens Lisa M.
Published: March 2024

Abstract
Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)–dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor–bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell–dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach.

Significance: These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell–dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy. Cancer Discovery; 1(1); 54–67. ©2011 AACR.

This article is highlighted in the In This Issue feature, p. 4
Data from Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma
Authors: Xue Wen , Meylan Etienne , Oliver Trudy G. , Feldser David M. , Winslow Monte M. , Bronson Roderick , Jacks Tyler
Published: March 2024

Abstract
Lung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-κB pathway affects both the initiation and the maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this investigation, we tested the efficacy of small-molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes, and rapidly induced apoptosis. Bortezomib also induced lung tumor regression and prolonged survival in tumor-bearing KrasLSL-G12D/wt;p53flox/flox mice but not in KrasLSL-G12D/wt mice. After repeated treatment, initially sensitive lung tumors became resistant to bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma.

Significance: Using small-molecule compounds that inhibit NF-κB activity, we provide evidence that NF-κB inhibition has therapeutic efficacy in the treatment of lung cancer. Our results also illustrate the value of mouse models in validating new drug targets in vivo and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer. Cancer Discovery; 1(3); 236–47. © 2011 AACR.

Read the Commentary on this article by Van Waes, p. 200

This article is highlighted in the In This Issue feature, p. 189
Data from A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors That Repress FGFR Signaling
Authors: Lin Ling , Chamberlain Lynn , Pak Magnolia L. , Nagarajan Arvindhan , Gupta Romi , Zhu Lihua J. , Wright Casey M. , Fong Kwun M. , Wajapeyee Narendra , Green Michael R.
Published: March 2024

Abstract
To discover new tumor-suppressor genes (TSG), we developed a functional genomics approach in which immortalized but nontumorigenic cells were stably transduced with large-scale shRNA pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly downregulated in human lung squamous cell carcinomas (hLSCC). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 amplification or activating mutations.

Significance: A functional genomics approach identifies new lung TSGs whose loss aberrantly increases FGFR signaling to promote tumorigenesis. These TSGs are frequently downregulated in hLSCCs, indicating that increased FGFR signaling promotes tumorigenesis in many hLSCCs lacking FGFR1 amplification or activating mutations. Cancer Discov; 4(10); 1168–81. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1103
Data from Stromal EGF and IGF-I Together Modulate Plasticity of Disseminated Triple-Negative Breast Tumors
Authors: Castaño Zafira , Marsh Timothy , Tadipatri Ramya , Kuznetsov Hanna S. , Al-Shahrour Fatima , Paktinat Mahnaz , Greene-Colozzi April , Nilsson Björn , Richardson Andrea L. , McAllister Sandra S.
Published: March 2024

Abstract
The causes for malignant progression of disseminated tumors and the reasons recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and show that recurrence rates are not strictly due to cell-intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with luminal breast cancer. Systemic signals provided by overt TNBCs cause the formation of a tumor-supportive microenvironment enriched for EGF and insulin-like growth factor-I (IGF-I) at distant indolent tumor sites. Bioavailability of EGF and IGF-I enhances the expression of transcription factors associated with pluripotency, proliferation, and epithelial–mesenchymal transition. Combinatorial therapy with EGF receptor and IGF-I receptor inhibitors prevents malignant progression. These results suggest that plasticity and recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for patients with TNBC.

Significance: Currently, processes that mediate progression of otherwise indolent tumors are not well understood, making it difficult to accurately predict which patients with cancer are likely to relapse. Our findings reveal novel mechanisms of tumor phenotypic and gene expression plasticity that are mandated by microenvironmental factors, identifying novel therapeutic targets for patients with TNBC. Cancer Discov; 3(8); 922–35. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 826
Data from Epithelial-to-Mesenchymal Transition Activates PERK–eIF2α and Sensitizes Cells to Endoplasmic Reticulum Stress
Authors: Feng Yu-xiong , Sokol Ethan S. , Del Vecchio Catherine A. , Sanduja Sandhya , Claessen Jasper H.L. , Proia Theresa A. , Jin Dexter X. , Reinhardt Ferenc , Ploegh Hidde L. , Wang Qiu , Gupta Piyush B.
Published: March 2024

Abstract
Epithelial-to-mesenchymal transition (EMT) promotes both tumor progression and drug resistance, yet few vulnerabilities of this state have been identified. Using selective small molecules as cellular probes, we show that induction of EMT greatly sensitizes cells to agents that perturb endoplasmic reticulum (ER) function. This sensitivity to ER perturbations is caused by the synthesis and secretion of large quantities of extracellular matrix (ECM) proteins by EMT cells. Consistent with their increased secretory output, EMT cells display a branched ER morphology and constitutively activate the PERK–eIF2α axis of the unfolded protein response (UPR). Protein kinase RNA-like ER kinase (PERK) activation is also required for EMT cells to invade and metastasize. In human tumor tissues, EMT gene expression correlates strongly with both ECM and PERK–eIF2α genes, but not with other branches of the UPR. Taken together, our findings identify a novel vulnerability of EMT cells, and demonstrate that the PERK branch of the UPR is required for their malignancy.

Significance: EMT drives tumor metastasis and drug resistance, highlighting the need for therapies that target this malignant subpopulation. Our findings identify a previously unrecognized vulnerability of cancer cells that have undergone an EMT: sensitivity to ER stress. We also find that PERK–eIF2α signaling, which is required to maintain ER homeostasis, is also indispensable for EMT cells to invade and metastasize. Cancer Discov; 4(6); 702–15. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 621
Data from Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation
Authors: Heinig Kristina , Gätjen Marcel , Grau Michael , Stache Vanessa , Anagnostopoulos Ioannis , Gerlach Kerstin , Niesner Raluca A. , Cseresnyes Zoltan , Hauser Anja E. , Lenz Peter , Hehlgans Thomas , Brink Robert , Westermann Jörg , Dörken Bernd , Lipp Martin , Lenz Georg , Rehm Armin , Höpken Uta E.
Published: March 2024

Abstract
In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell–like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin–β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin–β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli.

Significance: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma–leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor–stroma cross-talk. Cancer Discov; 4(12); 1448–65. ©2014 AACR.

See related commentary by López-Guerra et al., p. 1374

This article is highlighted in the In This Issue feature, p. 1355
Data from Unbiased Metabolite Profiling Indicates That a Diminished Thymidine Pool Is the Underlying Mechanism of Colon Cancer Chemoprevention by Alpha-Difluoromethylornithine
Authors: Witherspoon Mavee , Chen Qiuying , Kopelovich Levy , Gross Steven S. , Lipkin Steven M.
Published: March 2024

Abstract
The ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO) is a highly effective chemopreventive agent for colorectal cancer thought to act via polyamine depletion. However, in DFMO-treated patients, mucosal polyamine levels do not directly correlate with colorectal cancer risk. Untargeted metabolite profiling was used to broadly survey DFMO actions on colon cancer cell metabolism. We found that DFMO treatment of ApcMin intestinal tumors and human colorectal cancer cells is associated with reduced levels of folate-dependent metabolites, including S-adenosylmethionine (SAM), thymidine pools, and related pathway intermediates. We hypothesized that unrestrained SAM consumption/regeneration constitutes a futile DFMO-triggered cascade that can steal tetrahydrofolate from thymidylate synthase and thereby diminish thymidine pools. In accord with this hypothesis, DFMO treatment altered the folate cofactor balance and thymidine supplementation prevented DFMO-elicited cytostasis without restoring polyamine levels. These findings suggest that thymidine metabolite pool insufficiency is a fundamental mechanism of DFMO cytostatic activity.

Significance: A previously unappreciated metabolic linkage between polyamine and thymidine biosynthesis is revealed, based on the competing requirement of these pathways for a limited pool of tetrahydrofolate cofactor. This study identifies the first shared mechanism for colorectal cancer chemoprevention and chemotherapy, suggesting a common metabolic target for both premalignant and malignant colon cells. Cancer Discov; 3(9); 1072–81. ©2013 AACR.

See related commentary by Casero, p. 975

This article is highlighted in the In This Issue feature, p. 953
Data from A Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition
Authors: Shi Hubing , Hong Aayoung , Kong Xiangju , Koya Richard C. , Song Chunying , Moriceau Gatien , Hugo Willy , Yu Clarissa C. , Ng Charles , Chodon Thinle , Scolyer Richard A. , Kefford Richard F. , Ribas Antoni , Long Georgina V. , Lo Roger S.
Published: March 2024

Abstract
BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRβ), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K–AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1Q79K conferred BRAFi resistance via amplification of BRAFi-elicited PI3K–AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy.

Significance: This study provides a mechanistic link between early, adaptive and late, acquired BRAF inhibitor resistance in melanoma, with early BRAFi-induced signaling alterations shaping the subsequent evolutionary selective pressure. These findings argue for upfront, combined targeting of the mutant BRAF genotype and a pervasive drug-adaptive, AKT-dependent tumor response. Cancer Discov; 4(1); 69–79. ©2013 AACR.

See related commentary by Solit and Rosen, p. 27

This article is highlighted in the In This Issue feature, p. 1
Data from A High-Throughput Fluorimetric Assay for 2-Hydroxyglutarate Identifies Zaprinast as a Glutaminase Inhibitor
Authors: Elhammali Adnan , Ippolito Joseph E. , Collins Lynne , Crowley Jan , Marasa Jayne , Piwnica-Worms David
Published: March 2024

Abstract
Recently identified isocitrate dehydrogenase (IDH) mutations lead to the production of 2-hydroxyglutarate (2HG), an oncometabolite aberrantly elevated in selected cancers. We developed a facile and inexpensive fluorimetric microplate assay for the quantitation of 2HG and performed an unbiased small-molecule screen in live cells to identify compounds capable of perturbing 2HG production. Zaprinast, a phosphodiesterase 5 inhibitor, was identified as an efficacious modulator of 2HG production and confirmed to lower 2HG levels in vivo. The mechanism of action was not due to cGMP stabilization, but rather, profiling of metabolites upstream of mutant IDH1 pointed to targeted inhibition of the enzyme glutaminase (GLS). Zaprinast treatment reversed histone hypermethylation and soft-agar growth of IDH1-mutant cells, and treatment of glutamine-addicted pancreatic cancer cells reduced growth and sensitized cells to oxidative damage. Thus, Zaprinast is efficacious against glutamine metabolism and further establishes the therapeutic linkages between GLS and 2HG-mediated oncogenesis.

Significance: Gain-of-function IDH mutations are common events in glioma, acute myelogenous leukemia, and other cancer types, which lead to the accumulation of the oncometabolite 2HG. We show that the drug Zaprinast is capable of reducing cellular 2HG levels by inhibiting the upstream enzyme GLS, thus identifying a new strategy to target 2HG production in selected IDH-mutant cancers. Cancer Discov; 4(7); 828–39. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 745
Data from BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer
Authors: Chiou Shin-Heng , Risca Viviana I. , Wang Gordon X. , Yang Dian , Grüner Barbara M. , Kathiria Arwa S. , Ma Rosanna K. , Vaka Dedeepya , Chu Pauline , Kozak Margaret , Castellini Laura , Graves Edward E. , Kim Grace E. , Mourrain Philippe , Koong Albert C. , Giaccia Amato J. , Winslow Monte M.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character.

Significance: PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. Cancer Discov; 7(10); 1184–99. ©2017 AACR.

See related commentary by Vakoc and Tuveson, p. 1067.

This article is highlighted in the In This Issue feature, p. 1047
Data from Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer
Authors: Tricker Erin M. , Xu Chunxiao , Uddin Sharmeen , Capelletti Marzia , Ercan Dalia , Ogino Atsuko , Pratilas Christine A. , Rosen Neal , Gray Nathanael S. , Wong Kwok-Kin , Jänne Pasi A.
Published: March 2024

Abstract
Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor–resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFRT790M, prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002-sensitive models known to acquire resistance via both T790M-dependent and T790M-independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer.

Significance: Patients with EGFR-mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients. Cancer Discov; 5(9); 960–71. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 893
Data from Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression
Authors: Ogiwara Hideaki , Sasaki Mariko , Mitachi Takafumi , Oike Takahiro , Higuchi Saito , Tominaga Yuichi , Kohno Takashi
Published: March 2024

Abstract
Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300. Ablation of p300 in CBP-knockout and CBP-deficient cancer cells induced G1–S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers.

Significance: Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a “synthetic lethal–based therapeutic strategy” for CBP-deficient cancers by inhibition of the p300 HAT activity. Patients with CBP-deficient cancers could benefit from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430–45. ©2015 AACR.

See related commentary by Kadoch, p. 350.

This article is highlighted in the In This Issue feature, p. 331
Data from Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus–Host Protein Network
Authors: Eckhardt Manon , Zhang Wei , Gross Andrew M. , Von Dollen John , Johnson Jeffrey R. , Franks-Skiba Kathleen E. , Swaney Danielle L. , Johnson Tasha L. , Jang Gwendolyn M. , Shah Priya S. , Brand Toni M. , Archambault Jacques , Kreisberg Jason F. , Grandis Jennifer R. , Ideker Trey , Krogan Nevan J.
Published: March 2024

Abstract
We have mapped a global network of virus–host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV− but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers.

Significance: In this study, we created a protein–protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474–89. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1333
Data from Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse
Authors: Demaria Marco , O'Leary Monique N. , Chang Jianhui , Shao Lijian , Liu Su , Alimirah Fatouma , Koenig Kristin , Le Catherine , Mitin Natalia , Deal Allison M. , Alston Shani , Academia Emmeline C. , Kilmarx Sumner , Valdovinos Alexis , Wang Boshi , de Bruin Alain , Kennedy Brian K. , Melov Simon , Zhou Daohong , Sharpless Norman E. , Muss Hyman , Campisi Judith
Published: March 2024

Abstract
Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.

Significance: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165–76. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 115
Data from Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma
Authors: Chiron David , Di Liberto Maurizio , Martin Peter , Huang Xiangao , Sharman Jeff , Blecua Pedro , Mathew Susan , Vijay Priyanka , Eng Ken , Ali Siraj , Johnson Amy , Chang Betty , Ely Scott , Elemento Olivier , Mason Christopher E. , Leonard John P. , Chen-Kiang Selina
Published: March 2024

Abstract
Despite the unprecedented clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in mantle cell lymphoma (MCL), acquired resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K–AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired ibrutinib resistance in MCL and suggest a strategy to override both primary and acquired ibrutinib resistance.

Significance: We have discovered the first relapse-specific BTK mutation in patients with MCL with acquired resistance, but not primary resistance, to ibrutinib, and demonstrated a rationale for targeting the proliferative resistant MCL cells by inhibiting CDK4 and the cell cycle in combination with ibrutinib in the presence of BTKWT or a PI3K inhibitor independent of BTK mutation. As drug resistance remains a major challenge and CDK4 and PI3K are dysregulated at a high frequency in human cancers, targeting CDK4 in genome-based combination therapy represents a novel approach to lymphoma and cancer therapy. Cancer Discov; 4(9); 1022–35. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 973
Data from A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis
Authors: Ajona Daniel , Ortiz-Espinosa Sergio , Moreno Haritz , Lozano Teresa , Pajares María J. , Agorreta Jackeline , Bértolo Cristina , Lasarte Juan J. , Vicent Silvestre , Hoehlig Kai , Vater Axel , Lecanda Fernando , Montuenga Luis M. , Pio Ruben
Published: March 2024

Abstract
Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non–small cell lung cancer. We hypothesized that combined inhibition of C5a/C5aR1 and PD-1 signaling may have a synergistic antitumor effect. The RMP1-14 antibody was used to block PD-1, and an L-aptamer was used to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer, we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis and leads to prolonged survival. This effect is accompanied by a negative association between the frequency of CD8 T cells and myeloid-derived suppressor cells within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. Our study provides support for the clinical evaluation of anti–PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer.

Significance: Using a variety of preclinical models of lung cancer, we demonstrate that the blockade of C5a results in a substantial improvement in the efficacy of anti–PD-1 antibodies against lung cancer growth and metastasis. This study provides the preclinical rationale for the combined blockade of PD-1/PD-L1 and C5a to restore antitumor immune responses, inhibit tumor cell growth, and improve outcomes of patients with lung cancer. Cancer Discov; 7(7); 694–703. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 653
Data from Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial
Authors: Khan Khurum H. , Cunningham David , Werner Benjamin , Vlachogiannis Georgios , Spiteri Inmaculada , Heide Timon , Mateos Javier Fernandez , Vatsiou Alexandra , Lampis Andrea , Damavandi Mahnaz Darvish , Lote Hazel , Huntingford Ian Said , Hedayat Somaieh , Chau Ian , Tunariu Nina , Mentrasti Giulia , Trevisani Francesco , Rao Sheela , Anandappa Gayathri , Watkins David , Starling Naureen , Thomas Janet , Peckitt Clare , Khan Nasir , Rugge Massimo , Begum Ruwaida , Hezelova Blanka , Bryant Annette , Jones Thomas , Proszek Paula , Fassan Matteo , Hahne Jens C. , Hubank Michael , Braconi Chiara , Sottoriva Andrea , Valeri Nicola
Published: March 2024

Abstract
Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.

Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270–85. ©2018 AACR.

See related commentary by Siravegna and Corcoran, p. 1213.

This article is highlighted in the In This Issue feature, p. 1195
Data from IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma
Authors: Biffi Giulia , Oni Tobiloba E. , Spielman Benjamin , Hao Yuan , Elyada Ela , Park Youngkyu , Preall Jonathan , Tuveson David A.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors and extracellular matrix components, and have been implicated in PDAC progression and chemotherapy resistance. We recently identified two distinct CAF subtypes characterized by either myofibroblastic or inflammatory phenotypes; however, the mechanisms underlying their diversity and their roles in PDAC remain unknown. Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity. We show that IL1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs and demonstrate that TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts. Our results provide a mechanism through which distinct fibroblast niches are established in the PDAC microenvironment and illuminate strategies to selectively target CAFs that support tumor growth.
Significance:
Understanding the mechanisms that determine CAF heterogeneity in PDAC is a prerequisite for the rational development of approaches that selectively target tumor-promoting CAFs. Here, we identify an IL1-induced signaling cascade that leads to JAK/STAT activation and promotes an inflammatory CAF state, suggesting multiple strategies to target these cells in vivo.

See related commentary by Ling and Chiao, p. 173.

This article is highlighted in the In This Issue feature, p. 151
Data from A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105
Authors: Drilon Alexander , Fu Siqing , Patel Manish R. , Fakih Marwan , Wang Ding , Olszanski Anthony J. , Morgensztern Daniel , Liu Stephen V. , Cho Byoung Chul , Bazhenova Lyudmila , Rodriguez Cristina P. , Doebele Robert C. , Wozniak Antoinette , Reckamp Karen L. , Seery Tara , Nikolinakos Petros , Hu Zheyi , Oliver Jennifer W. , Trone Denise , McArthur Katherine , Patel Rupal , Multani Pratik S. , Ahn Myung-Ju
Published: March 2024

Abstract
RET fusions are oncogenic drivers of various tumors, including non–small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor–naïve patients with RET fusion–positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%–38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%–17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion–positive NSCLC), and 67% (95% CI, 30%–93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion–positive NSCLCs was not reached (range, 5 to 18+ months).
Significance:
Although KIF5B–RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non–KIF5B–RET-containing cancers. Novel approaches to targeting KIF5B–RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.

This article is highlighted in the In This Issue feature, p. 305
Data from An LKB1–SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation
Authors: Murray Christopher W. , Brady Jennifer J. , Tsai Min K. , Li Chuan , Winters Ian P. , Tang Rui , Andrejka Laura , Ma Rosanna K. , Kunder Christian A. , Chu Pauline , Winslow Monte M.
Published: March 2024

Abstract
The kinase LKB1 is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the tumor-suppressive capacity of four canonical families of LKB1 substrates in vivo, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic and gene-expression similarities between LKB1- and SIK-deficient tumors suggest that SIKs and LKB1 operate within the same axis. Furthermore, a gene-expression signature reflecting SIK deficiency is enriched in LKB1-mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these findings reveal a key LKB1–SIK tumor-suppressive axis and underscore the need to redirect efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression.
Significance:
Uncovering the effectors of frequently altered tumor suppressor genes is critical for understanding the fundamental driving forces of cancer growth. Our identification of the SIK family of kinases as effectors of LKB1-mediated tumor suppression will refocus future mechanistic studies and may lead to new avenues for genotype-specific therapeutic interventions.

This article is highlighted in the In This Issue feature, p. 1469
Data from Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer
Authors: Yoda Satoshi , Lin Jessica J. , Lawrence Michael S. , Burke Benjamin J. , Friboulet Luc , Langenbucher Adam , Dardaei Leila , Prutisto-Chang Kylie , Dagogo-Jack Ibiayi , Timofeevski Sergei , Hubbeling Harper , Gainor Justin F. , Ferris Lorin A. , Riley Amanda K. , Kattermann Krystina E. , Timonina Daria , Heist Rebecca S. , Iafrate A. John , Benes Cyril H. , Lennerz Jochen K. , Mino-Kenudson Mari , Engelman Jeffrey A. , Johnson Ted W. , Hata Aaron N. , Shaw Alice T.
Published: March 2024

Abstract
The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4–ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4–ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.

Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714–29. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 663
Data from Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer
Authors: Kitajima Shunsuke , Ivanova Elena , Guo Sujuan , Yoshida Ryohei , Campisi Marco , Sundararaman Shriram K. , Tange Shoichiro , Mitsuishi Yoichiro , Thai Tran C. , Masuda Sayuri , Piel Brandon P. , Sholl Lynette M. , Kirschmeier Paul T. , Paweletz Cloud P. , Watanabe Hideo , Yajima Mamiko , Barbie David A.
Published: March 2024

Abstract
KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL)–mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS-mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape.
Significance:
Oncogenic KRAS-mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype.

See related commentary by Corte and Byers, p. 16.

This article is highlighted in the In This Issue feature, p. 1
Data from HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development
Authors: de Bock Charles E. , Demeyer Sofie , Degryse Sandrine , Verbeke Delphine , Sweron Bram , Gielen Olga , Vandepoel Roel , Vicente Carmen , Vanden Bempt Marlies , Dagklis Antonis , Geerdens Ellen , Bornschein Simon , Gijsbers Rik , Soulier Jean , Meijerink Jules P. , Heinäniemi Merja , Teppo Susanna , Bouvy-Liivrand Maria , Lohi Olli , Radaelli Enrico , Cools Jan
Published: March 2024

Abstract
Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.

Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. Cancer Discov; 8(5); 616–31. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517