bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The BATTLE Trial: Personalizing Therapy for Lung Cancer
Authors: Kim Edward S. , Herbst Roy S. , Wistuba Ignacio I. , Lee J. Jack , Blumenschein George R. , Tsao Anne , Stewart David J. , Hicks Marshall E. , Erasmus Jeremy , Gupta Sanjay , Alden Christine M. , Liu Suyu , Tang Ximing , Khuri Fadlo R. , Tran Hai T. , Johnson Bruce E. , Heymach John V. , Mao Li , Fossella Frank , Kies Merrill S. , Papadimitrakopoulou Vassiliki , Davis Suzanne E. , Lippman Scott M. , Hong Waun K.
Published: March 2024

Abstract
The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non–small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. (ClinicalTrials.gov numbers: NCT00409968, NCT00411671, NCT00411632, NCT00410059, and NCT00410189.)

Significance: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with “real-time” biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment. Cancer Discovery; 1(1); 44–53. © 2011 AACR.

Read the Commentary on this article by Sequist et al., p. 14

Read the Commentary on this article by Rubin et al., p. 17

This article is highlighted in the In This Issue feature, p. 4
Data from BIM Expression in Treatment-Naïve Cancers Predicts Responsiveness to Kinase Inhibitors
Authors: Faber Anthony C. , Corcoran Ryan B. , Ebi Hiromichi , Sequist Lecia V. , Waltman Belinda A. , Chung Euiheon , Incio Joao , Digumarthy Subba R. , Pollack Sarah F. , Song Youngchul , Muzikansky Alona , Lifshits Eugene , Roberge Sylvie , Coffman Erik J. , Benes Cyril H. , Gómez Henry L. , Baselga José , Arteaga Carlos L. , Rivera Miguel N. , Dias-Santagata Dora , Jain Rakesh K. , Engelman Jeffrey A.
Published: March 2024

Abstract
Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is a wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment-naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.

Significance: In several oncogene-addiction paradigms, assessment of BIM RNA levels identifies those cancers that fail to have substantial apoptotic responses to kinase inhibitors. BIM RNA levels may be assessed in diagnostic cancer specimens to predict which patients will receive less benefit from single-agent kinase inhibitors. Cancer Discovery: 1(4); 352–65. ©2011 AACR.

Read the Commentary on this article by Yoshida and Haura, p. 289

This article is highlighted in the In This Issue feature, p. 275
Data from FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor
Authors: Guagnano Vito , Kauffmann Audrey , Wöhrle Simon , Stamm Christelle , Ito Moriko , Barys Louise , Pornon Astrid , Yao Yao , Li Fang , Zhang Yun , Chen Zhi , Wilson Christopher J. , Bordas Vincent , Le Douget Mickaël , Gaither L. Alex , Borawski Jason , Monahan John E. , Venkatesan Kavitha , Brümmendorf Thomas , Thomas David M. , Garcia-Echeverria Carlos , Hofmann Francesco , Sellers William R. , Graus-Porta Diana
Published: March 2024

Abstract
Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line–sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity.

Significance: The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov; 2(12); 1118–33. ©2012 AACR.

Read the Commentary on this article by Loch and Pollock, p. 1081

This article is highlighted in the In This Issue feature, p. 1065
Data from An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101
Authors: Doebele Robert C. , Davis Lara E. , Vaishnavi Aria , Le Anh T. , Estrada-Bernal Adriana , Keysar Stephen , Jimeno Antonio , Varella-Garcia Marileila , Aisner Dara L. , Li Yali , Stephens Philip J. , Morosini Deborah , Tuch Brian B. , Fernandes Michele , Nanda Nisha , Low Jennifer A.
Published: March 2024

Abstract
Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion–bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA–NTRK1 gene fusion encoding a functional LMNA–TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers.

Significance: TRK fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA–NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions. Cancer Discov; 5(10); 1049–57. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1005
Data from PRMT5 Is Required for Lymphomagenesis Triggered by Multiple Oncogenic Drivers
Authors: Li Yan , Chitnis Nilesh , Nakagawa Hiroshi , Kita Yoshiaki , Natsugoe Shoji , Yang Yi , Li Zihai , Wasik Mariusz , Klein-Szanto Andres J.P. , Rustgi Anil K. , Diehl J. Alan
Published: March 2024

Abstract
Protein arginine methyltransferase 5 (PRMT5) has been implicated as a key modulator of lymphomagenesis. Whether PRMT5 has overt oncogenic function in the context of leukemia/lymphoma and whether it represents a therapeutic target remains to be established. We demonstrate that inactivation of PRMT5 inhibits colony-forming activity by multiple oncogenic drivers, including cyclin D1, c-MYC, NOTCH1, and MLL–AF9. Furthermore, we demonstrate that PRMT5 overexpression specifically cooperates with cyclin D1 to drive lymphomagenesis in a mouse model, revealing inherent neoplastic activity. Molecular analysis of lymphomas revealed that arginine methylation of p53 selectively suppresses expression of crucial proapoptotic and antiproliferative target genes, thereby sustaining tumor cell self-renewal and proliferation and bypassing the need for the acquisition of inactivating p53 mutations. Critically, analysis of human tumor specimens reveals a strong correlation between cyclin D1 overexpression and p53 methylation, supporting the biomedical relevance of this pathway.

Significance: We have identified and functionally validated a crucial role for PRMT5 for the inhibition of p53-dependent tumor suppression in response to oncogenic insults. The requisite role for PRMT5 in the context of multiple lymphoma/leukemia oncogenic drivers suggests a molecular rationale for therapeutic development. Cancer Discov; 5(3); 288–303. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 213
Data from A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC
Authors: Dietlein Felix , Thelen Lisa , Jokic Mladen , Jachimowicz Ron D. , Ivan Laura , Knittel Gero , Leeser Uschi , van Oers Johanna , Edelmann Winfried , Heukamp Lukas C. , Reinhardt H. Christian
Published: March 2024

Abstract
Here, we use a large-scale cell line–based approach to identify cancer cell–specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination–mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects.

Significance: We associate mutations in the MSH3 gene, which are frequently detected in microsatellite-instable colon cancer (∼40%), with a therapeutic response to specific DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel opportunity to genetically stratify patients who may benefit from a DNA-PKcs–inhibitory therapy. Cancer Discov; 4(5); 592–605. ©2014 AACR.

See related commentary by Hemann, p. 516

This article is highlighted in the In This Issue feature, p. 495
Data from Elucidating Distinct Roles for NF1 in Melanomagenesis
Authors: Maertens Ophélia , Johnson Bryan , Hollstein Pablo , Frederick Dennie T. , Cooper Zachary A. , Messiaen Ludwine , Bronson Roderick T. , McMahon Martin , Granter Scott , Flaherty Keith , Wargo Jennifer A. , Marais Richard , Cichowski Karen
Published: March 2024

Abstract
BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal–regulated kinase pathways. As such, Nf1/Braf–mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal–regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.

Significance: This study elucidates the mechanism by which NF1 mutations cooperate with different BRAF mutations in melanomagenesis and shows that NF1/neurofibromin loss may desensitize tumors to BRAF inhibitors. Cancer Discov; 3(3); 338–49. ©2012 AACR.

See related commentary by Gibney and Smalley, p. 260

This article is highlighted in the In This Issue feature, p. 239
Data from Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
Authors: Shi Hubing , Hugo Willy , Kong Xiangju , Hong Aayoung , Koya Richard C. , Moriceau Gatien , Chodon Thinle , Guo Rongqing , Johnson Douglas B. , Dahlman Kimberly B. , Kelley Mark C. , Kefford Richard F. , Chmielowski Bartosz , Glaspy John A. , Sosman Jeffrey A. , van Baren Nicolas , Long Georgina V. , Ribas Antoni , Lo Roger S.
Published: March 2024

Abstract
BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K–PTEN–AKT–upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.

Significance: This study provides critical insights into how human BRAF-mutant melanoma, a malignancy with marked mutational burden, escapes from BRAF inhibitors. Understanding the core resistance pathways as well as tumor heterogeneity, fitness, and mutational patterns, which emerge under drug selection, lays a foundation to rationalize clinical studies and investigate mechanisms of disease progression. Cancer Discov; 4(1); 80–93. ©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 Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution
Authors: Dewhurst Sally M. , McGranahan Nicholas , Burrell Rebecca A. , Rowan Andrew J. , Grönroos Eva , Endesfelder David , Joshi Tejal , Mouradov Dmitri , Gibbs Peter , Ward Robyn L. , Hawkins Nicholas J. , Szallasi Zoltan , Sieber Oliver M. , Swanton Charles
Published: March 2024

Abstract
The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04–21.37; validation data: HR, 1.59, 95% CI, 1.05–2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution.

Significance: Our work sheds light on the importance of whole-genome–doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type. Cancer Discov; 4(2); 175–85. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 131
Data from Inhibition of KRAS-Driven Tumorigenicity by Interruption of an Autocrine Cytokine Circuit
Authors: Zhu Zehua , Aref Amir R. , Cohoon Travis J. , Barbie Thanh U. , Imamura Yu , Yang Shenghong , Moody Susan E. , Shen Rhine R. , Schinzel Anna C. , Thai Tran C. , Reibel Jacob B. , Tamayo Pablo , Godfrey Jason T. , Qian Zhi Rong , Page Asher N. , Maciag Karolina , Chan Edmond M. , Silkworth Whitney , Labowsky Mary T. , Rozhansky Lior , Mesirov Jill P. , Gillanders William E. , Ogino Shuji , Hacohen Nir , Gaudet Suzanne , Eck Michael J. , Engelman Jeffrey A. , Corcoran Ryan B. , Wong Kwok-Kin , Hahn William C. , Barbie David A.
Published: March 2024

Abstract
Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)–related kinases Tank-binding kinase-1 (TBK1) and IKKϵ promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKϵ inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKϵ promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKϵ, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.

Significance: In addition to activating MAPK and PI3K, oncogenic KRAS engages cytokine signaling to promote tumorigenesis. CYT387, originally described as a selective JAK inhibitor, is also a potent TBK/IKKϵ inhibitor that uniquely disrupts a cytokine circuit involving CCL5, IL-6, and STAT3. The efficacy of CYT387-based treatment in murine Kras-driven lung cancer models uncovers a novel therapeutic approach for these refractory tumors with immediate translational implications. Cancer Discov; 4(4); 452–65. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 377
Data from Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations
Authors: Ahronian Leanne G. , Sennott Erin M. , Van Allen Eliezer M. , Wagle Nikhil , Kwak Eunice L. , Faris Jason E. , Godfrey Jason T. , Nishimura Koki , Lynch Kerry D. , Mermel Craig H. , Lockerman Elizabeth L. , Kalsy Anuj , Gurski Joseph M. , Bahl Samira , Anderka Kristin , Green Lisa M. , Lennon Niall J. , Huynh Tiffany G. , Mino-Kenudson Mari , Getz Gad , Dias-Santagata Dora , Iafrate A. John , Engelman Jeffrey A. , Garraway Levi A. , Corcoran Ryan B.
Published: March 2024

Abstract
BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.

Significance: RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance. Cancer Discov; 5(4); 358–67. ©2015 AACR.

See related commentary by Meador and Pao, p. 348

This article is highlighted in the In This Issue feature, p. 333
Data from PDK1 Signaling Toward PLK1–MYC Activation Confers Oncogenic Transformation, Tumor-Initiating Cell Activation, and Resistance to mTOR-Targeted Therapy
Authors: Tan Jing , Li Zhimei , Lee Puay Leng , Guan Peiyong , Aau Mei Yee , Lee Shuet Theng , Feng Min , Lim Cheryl Zihui , Lee Eric Yong Jing , Wee Zhen Ning , Lim Yaw Chyn , Karuturi R.K. Murthy , Yu Qiang
Published: March 2024

Abstract
Although 3-phosphoinositide–dependent protein kinase-1 (PDK1) has been predominately linked to the phosphoinositide 3-kinase (PI3K)–AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1–PLK1–MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency. Intriguingly, PDK1–PLK1–MYC signaling induces an embryonic stem cell–like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self-renewal. Finally, we show that a PLK1 inhibitor synergizes with an mTOR inhibitor to induce synergistic antitumor effects in colorectal cancer by antagonizing compensatory MYC induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting MYC-associated tumorigenesis and therapeutic resistance.

Significance: This work identifies PDK1–PLK1–MYC signaling as a new oncogenic pathway driving oncogenic transformation and CSC self-renewal. Targeted inhibition of PDK1/PLK1 is robust in targeting MYC dependency in cancer cells. Thus, our findings provide important insights into cancer and CSC biology and have significant therapeutic implications. Cancer Discov; 3(10); 1156–71. ©2013 AACR.

See related commentary by Cunningham and Ruggero, p. 1099

This article is highlighted in the In This Issue feature, p. 1083
Data from Response of BRAF-Mutant Melanoma to BRAF Inhibition Is Mediated by a Network of Transcriptional Regulators of Glycolysis
Authors: Parmenter Tiffany J. , Kleinschmidt Margarete , Kinross Kathryn M. , Bond Simon T. , Li Jason , Kaadige Mohan R. , Rao Aparna , Sheppard Karen E. , Hugo Willy , Pupo Gulietta M. , Pearson Richard B. , McGee Sean L. , Long Georgina V. , Scolyer Richard A. , Rizos Helen , Lo Roger S. , Cullinane Carleen , Ayer Donald E. , Ribas Antoni , Johnstone Ricky W. , Hicks Rodney J. , McArthur Grant A.
Published: March 2024

Abstract
Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)–resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors.

Significance: BRAFis suppress glycolysis and provide strong clinical benefit in BRAFV600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. Cancer Discov; 4(4); 423–33. ©2014 AACR.

See related commentary by Haq, p. 390

This article is highlighted in the In This Issue feature, p. 377
Data from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
Authors: Karsli-Uzunbas Gizem , Guo Jessie Yanxiang , Price Sandy , Teng Xin , Laddha Saurabh V , Khor Sinan , Kalaany Nada Y. , Jacks Tyler , Chan Chang S. , Rabinowitz Joshua D. , White Eileen
Published: March 2024

Abstract
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer.

Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers. Cancer Discov; 4(8); 914–27. ©2014 AACR.

See related commentary by Amaravadi and Debnath, p. 873

This article is highlighted in the In This Issue feature, p. 855
Data from Comprehensive Genomic Profiling of Pancreatic Acinar Cell Carcinomas Identifies Recurrent RAF Fusions and Frequent Inactivation of DNA Repair Genes
Authors: Chmielecki Juliann , Hutchinson Katherine E. , Frampton Garrett M. , Chalmers Zachary R. , Johnson Adrienne , Shi Chanjuan , Elvin Julia , Ali Siraj M. , Ross Jeffrey S. , Basturk Olca , Balasubramanian Sohail , Lipson Doron , Yelensky Roman , Pao William , Miller Vincent A. , Klimstra David S. , Stephens Philip J.
Published: March 2024

Abstract
Pancreatic acinar cell carcinomas (PACC) account for approximately 1% (∼500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiotherapy have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n = 44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in approximately 23% of tumors. The most prevalent fusion, SND1–BRAF, resulted in activation of the MAPK pathway, which was abrogated with MEK inhibition. SND1–BRAF-transformed cells were sensitive to treatment with the MEK inhibitor trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations, causing inactivation of DNA repair genes (45%); these genomic alterations have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable genomic alterations in the majority of PACCs and provide a rationale for using personalized therapies in this disease.

Significance: PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors. Cancer Discov; 4(12); 1398–1405. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1355
Data from Pancreatic Cancer Metastases Harbor Evidence of Polyclonality
Authors: Maddipati Ravikanth , Stanger Ben Z.
Published: March 2024

Abstract
Studies of the cancer genome have demonstrated that tumors are composed of multiple subclones with varied genetic and phenotypic properties. However, little is known about how metastases arise and evolve from these subclones. To understand the cellular dynamics that drive metastasis, we used multicolor lineage-tracing technology in an autochthonous mouse model of pancreatic cancer. Here, we report that precursor lesions exhibit significant clonal heterogeneity but that this diversity decreases during premalignant progression. Furthermore, we present evidence that a significant fraction of metastases are polyclonally seeded by distinct tumor subclones. Finally, we show that clonality during metastatic growth—leading to either monoclonal or polyclonal expansion—differs based on the site of metastatic invasion. These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that heterotypic interactions between tumor subpopulations contribute to metastatic progression in native tumors.

Significance: Studies of tumor heterogeneity indicate that distinct tumor subclones interact during cancer progression. Here, we demonstrate by lineage tracing that metastases often involve seeding by more than one clone and that subsequent cellular outgrowth depends on the metastatic site. These findings provide insight into clonal diversity and evolution in metastatic disease. Cancer Discov; 5(10); 1086–97. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1005
Data from Identification of Targetable FGFR Gene Fusions in Diverse Cancers
Authors: Wu Yi-Mi , Su Fengyun , Kalyana-Sundaram Shanker , Khazanov Nickolay , Ateeq Bushra , Cao Xuhong , Lonigro Robert J. , Vats Pankaj , Wang Rui , Lin Su-Fang , Cheng Ann-Joy , Kunju Lakshmi P. , Siddiqui Javed , Tomlins Scott A. , Wyngaard Peter , Sadis Seth , Roychowdhury Sameek , Hussain Maha H. , Feng Felix Y. , Zalupski Mark M. , Talpaz Moshe , Pienta Kenneth J. , Rhodes Daniel R. , Robinson Dan R. , Chinnaiyan Arul M.
Published: March 2024

Abstract
Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types.

Significance: High-throughput sequencing technologies facilitate defining the mutational landscape of human cancers, which will lead to more precise treatment of patients with cancer. Here, through integrative sequencing efforts, we identified a variety of FGFR gene fusions in a spectrum of human cancers. FGFR fusions are active kinases. Cells harboring FGFR fusions showed enhanced sensitivity to the FGFR inhibitors PD173074 and pazopanib, suggesting that patients with cancer with FGFR fusions may benefit from targeted FGFR kinase inhibition. Cancer Discov; 3(6); 636–47. ©2013 AACR.

See related commentary by Sabnis and Bivona, p. 607

This article is highlighted in the In This Issue feature, p. 591
Data from Comprehensive Genomic Analysis of Rhabdomyosarcoma Reveals a Landscape of Alterations Affecting a Common Genetic Axis in Fusion-Positive and Fusion-Negative Tumors
Authors: Shern Jack F. , Chen Li , Chmielecki Juliann , Wei Jun S. , Patidar Rajesh , Rosenberg Mara , Ambrogio Lauren , Auclair Daniel , Wang Jianjun , Song Young K. , Tolman Catherine , Hurd Laura , Liao Hongling , Zhang Shile , Bogen Dominik , Brohl Andrew S. , Sindiri Sivasish , Catchpoole Daniel , Badgett Thomas , Getz Gad , Mora Jaume , Anderson James R. , Skapek Stephen X. , Barr Frederic G. , Meyerson Matthew , Hawkins Douglas S. , Khan Javed
Published: March 2024

Abstract
Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.

Significance: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention. Cancer Discov; 4(2); 216–31. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 131
Data from Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
Authors: Devlin Jennifer R. , Hannan Katherine M. , Hein Nadine , Cullinane Carleen , Kusnadi Eric , Ng Pui Yee , George Amee J. , Shortt Jake , Bywater Megan J. , Poortinga Gretchen , Sanij Elaine , Kang Jian , Drygin Denis , O'Brien Sean , Johnstone Ricky W. , McArthur Grant A. , Hannan Ross D. , Pearson Richard B.
Published: March 2024

Abstract
Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I–mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K–AKT–mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma–bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies.

Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1); 59–70. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles
Authors: Kim Eejung , Ilic Nina , Shrestha Yashaswi , Zou Lihua , Kamburov Atanas , Zhu Cong , Yang Xiaoping , Lubonja Rakela , Tran Nancy , Nguyen Cindy , Lawrence Michael S. , Piccioni Federica , Bagul Mukta , Doench John G. , Chouinard Candace R. , Wu Xiaoyun , Hogstrom Larson , Natoli Ted , Tamayo Pablo , Horn Heiko , Corsello Steven M. , Lage Kasper , Root David E. , Subramanian Aravind , Golub Todd R. , Getz Gad , Boehm Jesse S. , Hahn William C.
Published: March 2024

Abstract
Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild-type and mutant alleles, we inferred the activity of specific alleles. Because alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies.

Significance: Experimentally inferring the functional status of cancer-associated mutations facilitates the interpretation of genomic information in cancer. Pooled in vivo screen and gene expression profiling identified functional variants and demonstrated that expression of rare variants induced tumorigenesis. Variant phenotyping through functional studies will facilitate defining key somatic events in cancer. Cancer Discov; 6(7); 714–26. ©2016 AACR.

See related commentary by Cho and Collisson, p. 694.

This article is highlighted in the In This Issue feature, p. 681
Data from In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K–AKT Signaling at Endosomes
Authors: Li Chew Chen , Lunardi Andrea , Gulluni Federico , Ruan Daniel T. , Chen Ming , Salmena Leonardo , Nishino Michiya , Papa Antonella , Ng Christopher , Fung Jacqueline , Clohessy John G. , Sasaki Junko , Sasaki Takehiko , Bronson Roderick T. , Hirsch Emilio , Pandolfi Pier Paolo
Published: March 2024

Abstract
The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K–AKT signaling and are frequently dysregulated in human cancer. Although PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor-suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of Inpp4b morphs benign thyroid adenoma lesions in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC). Importantly, analyses of human thyroid cancer cell lines and specimens reveal INPP4B downregulation in FTC. Mechanistically, we find that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it selectively inhibits AKT2 activation and in turn tumor proliferation and anchorage-independent growth. We therefore identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of the PI3K–AKT pathway at the endosomes.

Significance: Although both PTEN and INPP4B can inhibit PI3K–AKT signaling through their lipid phosphatase activities, here we demonstrate lack of an epistatic relationship between the two tumor suppressors. Instead, the qualitative regulation of PI3K–AKT2 signaling by INPP4B provides a mechanism for their cooperation in suppressing thyroid tumorigenesis and metastasis. Cancer Discov; 5(7); 740–51. ©2015 AACR.

See related commentary by Vo and Fruman, p. 697.

See related article by Kofuji and colleagues, p. 730.

This article is highlighted in the In This Issue feature, p. 681
Data from Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer
Authors: Zhang Haikuo , Qi Jun , Reyes Jaime M. , Li Lewyn , Rao Prakash K. , Li Fugen , Lin Charles Y. , Perry Jennifer A. , Lawlor Matthew A. , Federation Alexander , De Raedt Thomas , Li Yvonne Y. , Liu Yan , Duarte Melissa A. , Zhang Yanxi , Herter-Sprie Grit S. , Kikuchi Eiki , Carretero Julian , Perou Charles M. , Reibel Jacob B. , Paulk Joshiawa , Bronson Roderick T. , Watanabe Hideo , Brainson Christine Fillmore , Kim Carla F. , Hammerman Peter S. , Brown Myles , Cichowski Karen , Long Henry , Bradner James E. , Wong Kwok-Kin
Published: March 2024

Abstract
As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non–small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways, leading to epigenetic transformation independent of canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a potent open-source EZH2 inhibitor, JQEZ5, that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer.

Significance: EZH2 overexpression induces murine lung cancers that are similar to human NSCLC with high EZH2 expression and low levels of phosphorylated AKT and ERK, implicating biomarkers for EZH2 inhibitor sensitivity. Our EZH2 inhibitor, JQEZ5, promotes regression of these tumors, revealing a potential role for anti-EZH2 therapy in lung cancer. Cancer Discov; 6(9); 1006–21. ©2016 AACR.

See related commentary by Frankel et al., p. 949.

This article is highlighted in the In This Issue feature, p. 932