bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms
Authors: Diamond Eli L. , Durham Benjamin H. , Haroche Julien , Yao Zhan , Ma Jing , Parikh Sameer A. , Wang Zhaoming , Choi John , Kim Eunhee , Cohen-Aubart Fleur , Lee Stanley Chun-Wei , Gao Yijun , Micol Jean-Baptiste , Campbell Patrick , Walsh Michael P. , Sylvester Brooke , Dolgalev Igor , Aminova Olga , Heguy Adriana , Zappile Paul , Nakitandwe Joy , Ganzel Chezi , Dalton James D. , Ellison David W. , Estrada-Veras Juvianee , Lacouture Mario , Gahl William A. , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Ali Siraj M. , Briggs Samuel R. , Fasan Omotayo , Block Jared , Héritier Sebastien , Donadieu Jean , Solit David B. , Hyman David M. , Baselga José , Janku Filip , Taylor Barry S. , Park Christopher Y. , Amoura Zahir , Dogan Ahmet , Emile Jean-Francois , Rosen Neal , Gruber Tanja A. , Abdel-Wahab Omar
Published: March 2024

Abstract
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.

Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 109
Data from A Coding Single-Nucleotide Polymorphism in Lysine Demethylase KDM4A Associates with Increased Sensitivity to mTOR Inhibitors
Authors: Van Rechem Capucine , Black Joshua C. , Greninger Patricia , Zhao Yang , Donado Carlos , Burrowes Paul d. , Ladd Brendon , Christiani David C. , Benes Cyril H. , Whetstine Johnathan R.
Published: March 2024

Abstract
SNPs occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence affect cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in subclassifying patients, and their impact on therapeutic response. In this report, we demonstrate that coding SNP-A482 within the lysine tridemethylase gene KDM4A/JMJD2A has different allelic frequencies across ethnic populations, associates with differential outcome in patients with non–small cell lung cancer (NSCLC), and promotes KDM4A protein turnover. Using an unbiased drug screen against 87 preclinical and clinical compounds, we demonstrate that homozygous SNP-A482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Our data emphasize the importance of using variant status as candidate biomarkers and highlight the importance of studying SNPs in chromatin modifiers to achieve better targeted therapy.

Significance: This report documents the first coding SNP within a lysine demethylase that associates with worse outcome in patients with NSCLC. We demonstrate that this coding SNP alters the protein turnover and associates with increased mTOR inhibitor sensitivity, which identifies a candidate biomarker for mTOR inhibitor therapy and a therapeutic target for combination therapy. Cancer Discov; 5(3); 245–54. ©2015 AACR.

See related commentary by Rothbart et al., p. 228

See related article by Van Rechem et al., p. 255

This article is highlighted in the In This Issue feature, p. 213
Data from NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function
Authors: Gough Sheryl M. , Lee Fan , Yang Fan , Walker Robert L. , Zhu Yeulin J. , Pineda Marbin , Onozawa Masahiro , Chung Yang Jo , Bilke Sven , Wagner Elise K. , Denu John M. , Ning Yi , Xu Bowen , Wang Gang Greg , Meltzer Paul S. , Aplan Peter D.
Published: March 2024

Abstract
In this report, we show that expression of a NUP98–PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and preleukemic tissues display a stem cell–like expression signature, including Hoxa, Hoxb, and Meis1 genes. The PHF23 plant homeodomain (PHD) motif is known to bind to H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein binds to chromatin at a specific subset of H3K4me3 sites, including at Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD motifs to H3K4me3, rapidly and selectively killed NP23-expressing myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98–JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.

Significance: NP23 and NJL belong to a subset of chromatin-modifying fusion oncoproteins that cause leukemia characterized by overexpression of Hoxa and Meis1 genes. Inhibition of NP23 binding to H3K4me3 at Hoxa and Meis1 loci by disulfiram, a U.S. Food and Drug Administration–approved drug, leads to leukemic cell death, demonstrating the feasibility of targeting this subset of oncoproteins. Cancer Discov; 4(5); 564–77. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 495
Data from Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
Authors: Skoulidis Ferdinandos , Byers Lauren A. , Diao Lixia , Papadimitrakopoulou Vassiliki A. , Tong Pan , Izzo Julie , Behrens Carmen , Kadara Humam , Parra Edwin R. , Canales Jaime Rodriguez , Zhang Jianjun , Giri Uma , Gudikote Jayanthi , Cortez Maria A. , Yang Chao , Fan Youhong , Peyton Michael , Girard Luc , Coombes Kevin R. , Toniatti Carlo , Heffernan Timothy P. , Choi Murim , Frampton Garrett M. , Miller Vincent , Weinstein John N. , Herbst Roy S. , Wong Kwok-Kin , Zhang Jianhua , Sharma Padmanee , Mills Gordon B. , Hong Waun K. , Minna John D. , Allison James P. , Futreal Andrew , Wang Jing , Wistuba Ignacio I. , Heymach John V.
Published: March 2024

Abstract
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP), and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further revealed biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules, and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant lung adenocarcinoma with distinct biology and therapeutic vulnerabilities.

Significance: Co-occurring genetic alterations in STK11/LKB1, TP53, and CDKN2A/B—the latter coupled with low TTF1 expression—define three major subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities. Cancer Discov; 5(8); 860–77. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 783
Data from Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis
Authors: Lunardi Andrea , Varmeh Shohreh , Chen Ming , Taulli Riccardo , Guarnerio Jlenia , Ala Ugo , Seitzer Nina , Ishikawa Tomoki , Carver Brett S. , Hobbs Robin M. , Quarantotti Valentina , Ng Christopher , Berger Alice H. , Nardella Caterina , Poliseno Laura , Montironi Rodolfo , Castillo-Martin Mireia , Cordon-Cardo Carlos , Signoretti Sabina , Pandolfi Pier Paolo
Published: March 2024

Abstract
The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members, such as ERG, ETV1, ETV4, and ETV5, are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here, we show that ETS family members, such as ERG and ETV1, directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA damage response cell-cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia into prostatic invasive carcinoma in Pten+/− mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications.

Significance: Genetic translocation and aberrant expression of ETS family members is a common event in different types of human tumors. Here, we show that through the transcriptional repression of CHK1, ETS factors may favor DNA damage accumulation and consequent genetic instability in proliferating cells. Importantly, our findings provide a rationale for testing DNA replication inhibitor agents in ETS-positive TP53-proficient tumors. Cancer Discov; 5(5); 550–63. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 453
Data from Vulnerabilities of PTEN–TP53-Deficient Prostate Cancers to Compound PARP–PI3K Inhibition
Authors: González-Billalabeitia Enrique , Seitzer Nina , Song Su Jung , Song Min Sup , Patnaik Akash , Liu Xue-Song , Epping Mirjam T. , Papa Antonella , Hobbs Robin M. , Chen Ming , Lunardi Andrea , Ng Christopher , Webster Kaitlyn A. , Signoretti Sabina , Loda Massimo , Asara John M. , Nardella Caterina , Clohessy John G. , Cantley Lewis C. , Pandolfi Pier Paolo
Published: March 2024

Abstract
Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K–AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53–deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer.

Significance: The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer. Cancer Discov; 4(8); 896–904. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 855
Data from Dual Roles of RNF2 in Melanoma Progression
Authors: Rai Kunal , Akdemir Kadir C. , Kwong Lawrence N. , Fiziev Petko , Wu Chang-Jiun , Keung Emily Z. , Sharma Sneha , Samant Neha S. , Williams Maura , Axelrad Jacob B. , Shah Amiksha , Yang Dong , Grimm Elizabeth A. , Barton Michelle C. , Milton Denai R. , Heffernan Timothy P. , Horner James W. , Ekmekcioglu Suhendan , Lazar Alexander J. , Ernst Jason , Chin Lynda
Published: March 2024

Abstract
Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is oncogenic and prometastatic. Mechanistically, RNF2-mediated invasive behavior is dependent on its ability to monoubiquitinate H2AK119 at the promoter of LTBP2, resulting in silencing of this negative regulator of TGFβ signaling. In contrast, RNF2′s oncogenic activity does not require its catalytic activity nor does it derive from its canonical gene repression function. Instead, RNF2 drives proliferation through direct transcriptional upregulation of the cell-cycle regulator CCND2. We further show that MEK1-mediated phosphorylation of RNF2 promotes recruitment of activating histone modifiers UTX and p300 to a subset of poised promoters, which activates gene expression. In summary, RNF2 regulates distinct biologic processes in the genesis and progression of melanoma via different molecular mechanisms.

Significance: The role of epigenetic regulators in cancer progression is being increasingly appreciated. We show novel roles for RNF2 in melanoma tumorigenesis and metastasis, albeit via different mechanisms. Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes. Cancer Discov; 5(12); 1314–27. ©2015 AACR.

See related commentary by Black and Whetstine, p. 1241.

This article is highlighted in the In This Issue feature, p. 1225
Data from PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex
Authors: Liu Pengda , Gan Wenjian , Chin Y. Rebecca , Ogura Kohei , Guo Jianping , Zhang Jinfang , Wang Bin , Blenis John , Cantley Lewis C. , Toker Alex , Su Bing , Wei Wenyi
Published: March 2024

Abstract
mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical SIN1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the SIN1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate AKT in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3.

Significance: The SIN1-PH domain interacts with the mTOR kinase domain to suppress mTOR activity, and PtdIns(3,4,5)P3 binds the SIN1-PH domain to release its inhibition on the mTOR kinase domain, leading to mTORC2 activation. Cancer patient–derived SIN1-PH domain mutations gain oncogenicity by loss of suppressing mTOR activity as a means to facilitate tumorigenesis. Cancer Discov; 5(11); 1194–209. ©2015 AACR.

See related commentary by Yuan and Guan, p. 1127.

This article is highlighted in the In This Issue feature, p. 1111
Data from Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma
Authors: Maity Tapan K. , Venugopalan Abhilash , Linnoila Ilona , Cultraro Constance M. , Giannakou Andreas , Nemati Roxanne , Zhang Xu , Webster Joshua D. , Ritt Daniel , Ghosal Sarani , Hoschuetzky Heinz , Simpson R. Mark , Biswas Romi , Politi Katerina , Morrison Deborah K. , Varmus Harold E. , Guha Udayan
Published: March 2024

Abstract
Somatic mutations in the EGFR kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here, we demonstrate that MIG6 is a tumor suppressor for the initiation and progression of mutant EGFR–driven lung adenocarcinoma in mouse models. Mutant EGFR–induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/Y395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for MIG6 to delay mutant EGFR–driven tumor initiation and progression in mouse models.

Significance: This study demonstrates that MIG6 is a potent tumor suppressor for mutant EGFR–driven lung tumor initiation and progression in mice and provides a possible mechanism by which mutant EGFR can partially circumvent this tumor suppressor in human lung adenocarcinoma. Cancer Discov; 5(5); 534–49. ©2015 AACR.

See related commentary by Izumchenko and Sidransky, p. 472.

This article is highlighted in the In This Issue feature, p. 453
Data from The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Authors: Friboulet Luc , Li Nanxin , Katayama Ryohei , Lee Christian C. , Gainor Justin F. , Crystal Adam S. , Michellys Pierre-Yves , Awad Mark M. , Yanagitani Noriko , Kim Sungjoon , Pferdekamper AnneMarie C. , Li Jie , Kasibhatla Shailaja , Sun Frank , Sun Xiuying , Hua Su , McNamara Peter , Mahmood Sidra , Lockerman Elizabeth L. , Fujita Naoya , Nishio Makoto , Harris Jennifer L. , Shaw Alice T. , Engelman Jeffrey A.
Published: March 2024

Abstract
Non–small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.

Significance: The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. Cancer Discov; 4(6); 662–73. ©2014 AACR.

See related commentary by Ramalingam and Khuri, p. 634

This article is highlighted in the In This Issue feature, p. 621
Data from Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas
Authors: Zill Oliver A. , Greene Claire , Sebisanovic Dragan , Siew Lai Mun , Leng Jim , Vu Mary , Hendifar Andrew E. , Wang Zhen , Atreya Chloe E. , Kelley Robin K. , Van Loon Katherine , Ko Andrew H. , Tempero Margaret A. , Bivona Trever G. , Munster Pamela N. , Talasaz AmirAli , Collisson Eric A.
Published: March 2024

Abstract
Patients with pancreatic and biliary carcinomas lack personalized treatment options, in part because biopsies are often inadequate for molecular characterization. Cell-free DNA (cfDNA) sequencing may enable a precision oncology approach in this setting. We attempted to prospectively analyze 54 genes in tumor and cfDNA for 26 patients. Tumor sequencing failed in 9 patients (35%). In the remaining 17, 90.3% (95% confidence interval, 73.1%–97.5%) of mutations detected in tumor biopsies were also detected in cfDNA. The diagnostic accuracy of cfDNA sequencing was 97.7%, with 92.3% average sensitivity and 100% specificity across five informative genes. Changes in cfDNA correlated well with tumor marker dynamics in serial sampling (r = 0.93). We demonstrate that cfDNA sequencing is feasible, accurate, and sensitive in identifying tumor-derived mutations without prior knowledge of tumor genotype or the abundance of circulating tumor DNA. cfDNA sequencing should be considered in pancreatobiliary cancer trials where tissue sampling is unsafe, infeasible, or otherwise unsuccessful.

Significance: Precision medicine efforts in biliary and pancreatic cancers have been frustrated by difficulties in obtaining adequate tumor tissue for next-generation sequencing. cfDNA sequencing reliably and accurately detects tumor-derived mutations, paving the way for precision oncology approaches in these deadly diseases. Cancer Discov; 5(10); 1040–8. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1005
Data from Mcl-1 and FBW7 Control a Dominant Survival Pathway Underlying HDAC and Bcl-2 Inhibitor Synergy in Squamous Cell Carcinoma
Authors: He Lei , Torres-Lockhart Kristine , Forster Nicole , Ramakrishnan Saranya , Greninger Patricia , Garnett Mathew J. , McDermott Ultan , Rothenberg Stephen M. , Benes Cyril H. , Ellisen Leif W.
Published: March 2024

Abstract
Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3-mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with the combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.

Significance: This study reveals the tissue-specific landscape and biochemistry of the Bcl-2 family in SCC, which underlie moderate sensitivity of these tumors to HDAC inhibitor therapy but dramatic synergy in combination with BH3-mimetic therapy. By establishing predictive biomarkers, we provide evidence that tumors most likely to respond to this therapeutic combination, including those harboring somatic FBW7 mutations, are those most resistant to standard chemotherapy. Cancer Discov; 3(3); 324–37. ©2012 AACR.

See related commentary by Pickering and Myers, p. 258

This article is highlighted in the In This Issue feature, p. 239
Data from Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets
Authors: Balko Justin M. , Giltnane Jennifer M. , Wang Kai , Schwarz Luis J. , Young Christian D. , Cook Rebecca S. , Owens Phillip , Sanders Melinda E. , Kuba Maria G. , Sánchez Violeta , Kurupi Richard , Moore Preston D. , Pinto Joseph A. , Doimi Franco D. , Gómez Henry , Horiuchi Dai , Goga Andrei , Lehmann Brian D. , Bauer Joshua A. , Pietenpol Jennifer A. , Ross Jeffrey S. , Palmer Gary A. , Yelensky Roman , Cronin Maureen , Miller Vincent A. , Stephens Phillip J. , Arteaga Carlos L.
Published: March 2024

Abstract
Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC.

Significance: This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted therapies immediately after mastectomy before these metastases become evident. Cancer Discov; 4(2); 232–45. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 131
Data from Combined Inhibition of MAP Kinase and KIT Signaling Synergistically Destabilizes ETV1 and Suppresses GIST Tumor Growth
Authors: Ran Leili , Sirota Inna , Cao Zhen , Murphy Devan , Chen Yuedan , Shukla Shipra , Xie Yuanyuan , Kaufmann Michael C. , Gao Dong , Zhu Sinan , Rossi Ferdinando , Wongvipat John , Taguchi Takahiro , Tap William D. , Mellinghoff Ingo K. , Besmer Peter , Antonescu Cristina R. , Chen Yu , Chi Ping
Published: March 2024

Abstract
Gastrointestinal stromal tumor (GIST), originating from the interstitial cells of Cajal (ICC), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib, which targets KIT, most patients with advanced GIST develop resistance and eventually die of the disease. The ETS family transcription factor ETV1 is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein, and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumor regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management.

Significance: ETV1 is a lineage-specific oncogenic transcription factor required for the growth and survival of GIST. We describe a novel strategy of targeting ETV1 protein stability by the combination of MEK and KIT inhibitors that synergistically suppress tumor growth. This strategy has the potential to change first-line therapy in GIST clinical management. Cancer Discov; 5(3); 304–15. ©2015 AACR.

See related commentary by Duensing, p. 231

This article is highlighted in the In This Issue feature, p. 213
Data from Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype
Authors: Paraiso Kim H.T. , Thakur Meghna Das , Fang Bin , Koomen John M. , Fedorenko Inna V. , John Jobin K. , Tsao Hensin , Flaherty Keith T. , Sondak Vernon K. , Messina Jane L. , Pasquale Elena B. , Villagra Alejandro , Rao Uma N. , Kirkwood John M. , Meier Friedegund , Sloot Sarah , Gibney Geoffrey T. , Stuart Darrin , Tawbi Hussein , Smalley Keiran S.M.
Published: March 2024

Abstract
Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.

Significance: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. Cancer Discov; 5(3); 264–73. ©2014 AACR.

See related article by Miao et al., p. 274

This article is highlighted in the In This Issue feature, p. 213
Data from SPSB1 Promotes Breast Cancer Recurrence by Potentiating c-MET Signaling
Authors: Feng Yi , Pan Tien-Chi , Pant Dhruv K. , Chakrabarti Kristi R. , Alvarez James V. , Ruth Jason R. , Chodosh Lewis A.
Published: March 2024

Abstract
Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer.

Significance: The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1–c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacologic targets for recurrence may be unique to this stage of tumor progression. Cancer Discov; 4(7); 790–803. ©2014 AACR.

See related commentary by Qin and McAllister, p. 760

This article is highlighted in the In This Issue feature, p. 745
Data from ATM Regulates 3-Methylpurine-DNA Glycosylase and Promotes Therapeutic Resistance to Alkylating Agents
Authors: Agnihotri Sameer , Burrell Kelly , Buczkowicz Pawel , Remke Marc , Golbourn Brian , Chornenkyy Yevgen , Gajadhar Aaron , Fernandez Nestor A. , Clarke Ian D. , Barszczyk Mark S. , Pajovic Sanja , Ternamian Christian , Head Renee , Sabha Nesrin , Sobol Robert W. , Taylor Michael D. , Rutka James T. , Jones Chris , Dirks Peter B. , Zadeh Gelareh , Hawkins Cynthia
Published: March 2024

Abstract
Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent–induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM–MPG axis will lead to improved treatment of alkylating agent–resistant tumors.

Significance: Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window. Cancer Discov; 4(10); 1198–1213. ©2014 AACR.

See related commentary by Wick and Platten, p. 1120

This article is highlighted in the In This Issue feature, p. 1103
Data from Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome–Spectrum Cancers
Authors: Park Daniel J. , Tao Kayoko , Le Calvez-Kelm Florence , Nguyen-Dumont Tu , Robinot Nivonirina , Hammet Fleur , Odefrey Fabrice , Tsimiklis Helen , Teo Zhi L. , Thingholm Louise B. , Young Erin L. , Voegele Catherine , Lonie Andrew , Pope Bernard J. , Roane Terrell C. , Bell Russell , Hu Hao , Huff Chad D. , Ellis Jonathan , Li Jun , Makunin Igor V. , John Esther M. , Andrulis Irene L. , Terry Mary B. , Daly Mary , Buys Saundra S. , Snyder Carrie , Lynch Henry T. , Devilee Peter , Giles Graham G. , Hopper John L. , Feng Bing-Jian , Lesueur Fabienne , Tavtigian Sean V. , Southey Melissa C. , Goldgar David E.
Published: March 2024

Abstract
Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case–control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29–8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome–spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7–6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7–21; P = 0.0003).

Significance: The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions. Cancer Discov; 4(7); 804–15. ©2014 AACR.

See related commentary by Ngeow and Eng, p. 762

This article is highlighted in the In This Issue feature, p. 745
Data from A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity
Authors: Shono Yusuke , Tuckett Andrea Z. , Ouk Samedy , Liou Hsiou-Chi , Altan-Bonnet Grégoire , Tsai Jennifer J. , Oyler Jennifer E. , Smith Odette M. , West Mallory L. , Singer Natalie V. , Doubrovina Ekaterina , Pankov Dmitry , Undhad Chandresh V. , Murphy George F. , Lezcano Cecilia , Liu Chen , O'Reilly Richard J. , van den Brink Marcel R.M. , Zakrzewski Johannes L.
Published: March 2024

Abstract
Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule–based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel–deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.

Significance: Chemical inhibition of c-Rel diminishes alloactivation while preserving antigen-specific TCR activation, revealing the redundancy of c-Rel in T cell–mediated antitumor activity of both mouse and human T cells. Our study provides a highly innovative immunomodulatory approach that has true potential for drug development and clinical application with broad therapeutic implications, including allo-tolerance induction after allo-HSCT, as well as antitumor therapies. Cancer Discov; 4(5); 578–91. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 495
Data from Systematic Interrogation of 3q26 Identifies TLOC1 and SKIL as Cancer Drivers
Authors: Hagerstrand Daniel , Tong Alexander , Schumacher Steven E. , Ilic Nina , Shen Rhine R. , Cheung Hiu Wing , Vazquez Francisca , Shrestha Yashaswi , Kim So Young , Giacomelli Andrew O. , Rosenbluh Joseph , Schinzel Anna C. , Spardy Nicole A. , Barbie David A. , Mermel Craig H. , Weir Barbara A. , Garraway Levi A. , Tamayo Pablo , Mesirov Jill P. , Beroukhim Rameen , Hahn William C.
Published: March 2024

Abstract
3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage-independent growth, and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells. Expression of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies showed that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through upregulation of SLUG (SNAI2) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplified in other regions with somatic copy number gain.

Significance: These studies identify TLOC1 and SKIL as driver genes in 3q26. These observations provide evidence that regions of somatic copy number gain may harbor cooperating genes of different but complementary functions. Cancer Discov; 3(9); 1044–57. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 953
Data from Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation
Authors: Xu Jin , Haigis Kevin M. , Firestone Ari J. , McNerney Megan E. , Li Qing , Davis Elizabeth , Chen Shann-Ching , Nakitandwe Joy , Downing James , Jacks Tyler , Le Beau Michelle M. , Shannon Kevin
Published: March 2024

Abstract
Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic NrasG12D in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased NrasG12D gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of NrasG12D/G12D hematopoietic cells. Modulating NrasG12D dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous NrasG12D. Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers.

Significance: Understanding the mechanisms of Ras-induced transformation and adaptive cellular responses is fundamental. The observation that oncogenic Nras lacks tumor suppressor activity, whereas increased dosage strongly modulates cell growth and alters sensitivity to MEK inhibition, suggests new therapeutic opportunities in cancer. Cancer Discov; 3(9); 993–1001. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 953
Data from Polarization of Tissue-Resident TFH-Like Cells in Human Hepatoma Bridges Innate Monocyte Inflammation and M2b Macrophage Polarization
Authors: Chen Min-Min , Xiao Xiao , Lao Xiang-Ming , Wei Yuan , Liu Rui-Xian , Zeng Qiu-Hui , Wang Jun-Cheng , Ouyang Fang-Zhu , Chen Dong-Ping , Chan Ka-Wo , Shi Dai-Chao , Zheng Limin , Kuang Dong-Ming
Published: March 2024

Abstract
The existence, regulation, and functions of IL21+ immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21+ TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL21 in tumors and represented about 10% of the CD4+ T-cell population at levels comparable with the TFH cells present in lymph nodes. However, these TFH-like cells displayed a unique CXCR5−PD-1lo/−BTLA−CD69hi tissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of TFH cells. Toll-like receptor 4 (TLR4)–elicited innate monocyte inflammation was important for IL21+ TFH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for TFH-like cell polarization in this process. Importantly, the TFH-like cells operated in IL21–IFNγ-dependent pathways to induce plasma cell differentiation and thereby create conditions for protumorigenic M2b macrophage polarization and cancer progression. Thus, induction of TFH-like cells links innate inflammation to immune privilege in tumors.

Significance: We identified a novel protumorigenic IL21+ TFH-like cell subset with a CXCR5−PD-1− BTLA−CD69hi tissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for TFH-like cell induction. TFH-like cells operate via IL21–IFNγ pathways to induce plasma cells and create conditions for M2b macrophage polarization. Cancer Discov; 6(10); 1182–95. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1069
Data from Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression
Authors: Wang Guocan , Lu Xin , Dey Prasenjit , Deng Pingna , Wu Chia Chin , Jiang Shan , Fang Zhuangna , Zhao Kun , Konaparthi Ramakrishna , Hua Sujun , Zhang Jianhua , Li-Ning-Tapia Elsa M. , Kapoor Avnish , Wu Chang-Jiun , Patel Neelay Bhaskar , Guo Zhenglin , Ramamoorthy Vandhana , Tieu Trang N. , Heffernan Tim , Zhao Di , Shang Xiaoying , Khadka Sunada , Hou Pingping , Hu Baoli , Jin Eun-Jung , Yao Wantong , Pan Xiaolu , Ding Zhihu , Shi Yanxia , Li Liren , Chang Qing , Troncoso Patricia , Logothetis Christopher J. , McArthur Mark J. , Chin Lynda , Wang Y. Alan , DePinho Ronald A.
Published: March 2024

Abstract
The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo–YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP–TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5–CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer.

Significance: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo–YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5–CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival. Cancer Discov; 6(1); 80–95. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1