bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509
Authors: Joseph James D. , Lu Nhin , Qian Jing , Sensintaffar John , Shao Gang , Brigham Dan , Moon Michael , Maneval Edna Chow , Chen Isan , Darimont Beatrice , Hager Jeffrey H.
Published: March 2024

Abstract
Despite the impressive clinical activity of the second-generation antiandrogens enzalutamide and ARN-509 in patients with prostate cancer, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity due to a missense mutation (F876L) in the ligand-binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of castration-resistant prostate cancer (CRPC). Importantly, the AR F876L mutant is detected in plasma DNA from ARN-509–treated patients with progressive CRPC. Thus, selective outgrowth of AR F876L is a clinically relevant mechanism of second-generation antiandrogen resistance that can potentially be targeted with next-generation antiandrogens.

Significance: A missense mutation in the ligand-binding domain of the androgen receptor F876L confers resistance to the second-generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARN-509–treated patients with progressive disease. These results chart a new path for the discovery and development of next-generation antiandrogens that could be coupled with a blood-based companion diagnostic to guide treatment decisions. Cancer Discov; 3(9); 1020–9. ©2013 AACR.

See related commentary by Nelson and Yegnasubramanian, p. 971

This article is highlighted in the In This Issue feature, p. 953
Data from p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis
Authors: Alspach Elise , Flanagan Kevin C. , Luo Xianmin , Ruhland Megan K. , Huang Hui , Pazolli Ermira , Donlin Maureen J. , Marsh Timothy , Piwnica-Worms David , Monahan Joseph , Novack Deborah V. , McAllister Sandra S. , Stewart Sheila A.
Published: March 2024

Abstract
Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here, we address a key unanswered question: how the SASP is sustained in senescent fibroblasts and CAFs. We find that the mitogen-activated protein kinase p38 (p38MAPK) controls AUF1 occupancy on SASP mRNAs and thus controls their stability. The importance of this regulatory mechanism is underscored by our findings that stromal-specific p38MAPK inhibition abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Our data suggest that targeting SASP mRNA stability through inhibition of p38MAPK will significantly aid the development of clinical strategies to target the TME.

Significance: The TME plays a key role in tumorigenesis. We demonstrate that p38MAPK governs a posttranscriptional mechanism that sustains the protumorigenic SASP. Inhibition of p38MAPK abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Thus, p38MAPK is a TME-specific Achilles' heel that may be exploited as a new therapeutic target. Cancer Discov; 4(6); 716–29. ©2014 AACR.

See related commentary by Isacke and Barcellos-Hoff, p. 637

This article is highlighted in the In This Issue feature, p. 621
Data from PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression
Authors: Xiao Xiao , Lao Xiang-Ming , Chen Min-Min , Liu Rui-Xian , Wei Yuan , Ouyang Fang-Zhu , Chen Dong-Ping , Zhao Xiao-Yu , Zhao Qiyi , Li Xue-Feng , Liu Chuan-Lu , Zheng Limin , Kuang Dong-Ming
Published: March 2024

Abstract
B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 downregulate inflammation and control T-cell immunity. Here, we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ∼10% of all B cells in advanced-stage hepatocellular carcinoma (HCC). These PD-1hi B cells exhibited a unique CD5hiCD24−/+CD27hi/+CD38dim phenotype different from the phenotype of conventional CD24hiCD38hi peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1hi B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1+ cells or undergoing PD-1 triggering, PD-1hi B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1.

Significance: We identify a novel protumorigenic PD-1hi B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1hi B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546–59. ©2016 AACR.

See related commentary by Ren et al., p. 477.

This article is highlighted in the In This Issue feature, p. 461
Data from HOXB7 Is an ERα Cofactor in the Activation of HER2 and Multiple ER Target Genes Leading to Endocrine Resistance
Authors: Jin Kideok , Park Sunju , Teo Wei Wen , Korangath Preethi , Cho Sean Soonweng , Yoshida Takahiro , Győrffy Balázs , Goswami Chirayu Pankaj , Nakshatri Harikrishna , Cruz Leigh-Ann , Zhou Weiqiang , Ji Hongkai , Su Ying , Ekram Muhammad , Wu Zhengsheng , Zhu Tao , Polyak Kornelia , Sukumar Saraswati
Published: March 2024

Abstract
Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor-α (ERα) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 chromatin immunoprecipitation analysis followed by validation showed that HOXB7 physically interacts with ERα, and that the HOXB7–ERα complex enhances transcription of many ERα target genes, including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR–HER2 signaling, inhibits transcription of miR-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER target genes, and HER2. Repressing MYC using small-molecule inhibitors reverses these events and causes regression of breast cancer xenografts. The MYC–HOXB7–HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer.

Significance: HOXB7 acts as an ERα cofactor regulating a myriad of ER target genes, including HER2, in tamoxifen-resistant breast cancer. HOXB7 expression is controlled by MYC via transcriptional regulation of the HOXB7 repressor miR-196a; consequently, antagonists of MYC cause reversal of selective ER modulator resistance both in vitro and in vivo. Cancer Discov; 5(9); 944–59. ©2015 AACR.

See related commentary by Heideman et al., p. 909.

This article is highlighted in the In This Issue feature, p. 893
Data from Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy
Authors: Blake Stephen J. , Stannard Kimberley , Liu Jing , Allen Stacey , Yong Michelle C.R. , Mittal Deepak , Aguilera Amelia Roman , Miles John J. , Lutzky Viviana P. , de Andrade Lucas Ferrari , Martinet Ludovic , Colonna Marco , Takeda Kazuyoshi , Kühnel Florian , Gurlevik Engin , Bernhardt Günter , Teng Michele W.L. , Smyth Mark J.
Published: March 2024

Abstract
CD96 has recently been shown as a negative regulator of mouse natural killer (NK)–cell activity, with Cd96−/− mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different tumor models. The antimetastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1), and IFNγ, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti–CTLA-4, anti–PD-1, or doxorubicin chemotherapy. Blocking CD96 in Tigit−/− mice significantly reduced experimental and spontaneous metastases compared with its activity in wild-type mice. Co-blockade of CD96 and PD-1 potently inhibited lung metastases, with the combination increasing local NK-cell IFNγ production and infiltration. Overall, these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases.

Significance: This article illustrates the antimetastatic activity and mechanism of action of an anti-CD96 antibody that inhibits the CD96–CD155 interaction and stimulates NK-cell function. Targeting host CD96 is shown to complement surgery and conventional immune checkpoint blockade. Cancer Discov; 6(4); 446–59. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 331
Data from INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor
Authors: Kofuji Satoshi , Kimura Hirotaka , Nakanishi Hiroki , Nanjo Hiroshi , Takasuga Shunsuke , Liu Hui , Eguchi Satoshi , Nakamura Ryotaro , Itoh Reietsu , Ueno Noriko , Asanuma Ken , Huang Mingguo , Koizumi Atsushi , Habuchi Tomonori , Yamazaki Masakazu , Suzuki Akira , Sasaki Junko , Sasaki Takehiko
Published: March 2024

Abstract
Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4bΔ/Δ) nor heterozygous deletion of Pten (Pten+/−) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a “back-up” mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers.

Significance: Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3. Cancer Discov; 5(7); 730–9. ©2015 AACR.

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

See related article by Chew et al., p. 740.

This article is highlighted in the In This Issue feature, p. 681
Data from Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade
Authors: Chen Pei-Ling , Roh Whijae , Reuben Alexandre , Cooper Zachary A. , Spencer Christine N. , Prieto Peter A. , Miller John P. , Bassett Roland L. , Gopalakrishnan Vancheswaran , Wani Khalida , De Macedo Mariana Petaccia , Austin-Breneman Jacob L. , Jiang Hong , Chang Qing , Reddy Sangeetha M. , Chen Wei-Shen , Tetzlaff Michael T. , Broaddus Russell J. , Davies Michael A. , Gershenwald Jeffrey E. , Haydu Lauren , Lazar Alexander J. , Patel Sapna P. , Hwu Patrick , Hwu Wen-Jen , Diab Adi , Glitza Isabella C. , Woodman Scott E. , Vence Luis M. , Wistuba Ignacio I. , Amaria Rodabe N. , Kwong Lawrence N. , Prieto Victor , Davis R. Eric , Ma Wencai , Overwijk Willem W. , Sharpe Arlene H. , Hu Jianhua , Futreal P. Andrew , Blando Jorge , Sharma Padmanee , Allison James P. , Chin Lynda , Wargo Jennifer A.
Published: March 2024

Abstract
Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified.

Significance: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827–37. ©2016 AACR.

See related commentary by Teng et al., p. 818.

This article is highlighted in the In This Issue feature, p. 803
Data from Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease
Authors: Liu Jing , Blake Stephen J. , Yong Michelle C.R. , Harjunpää Heidi , Ngiow Shin Foong , Takeda Kazuyoshi , Young Arabella , O'Donnell Jake S. , Allen Stacey , Smyth Mark J. , Teng Michele W.L.
Published: March 2024

Abstract
Immunotherapy has recently entered a renaissance phase with the approval of multiple agents for the treatment of cancer. Immunotherapy stands ready to join traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as a pillar of cancer treatment. Although immunotherapy has begun to have success in advanced cancer treatment, its scheduling and efficacy with surgery to treat earlier stages of cancer and prevent distant metastases have not been systematically examined. Here, we have used two models of spontaneously metastatic breast cancers in mice to illustrate the significantly greater therapeutic power of neoadjuvant, compared with adjuvant, immunotherapies in the context of primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior to and post surgery may provide a predictor of outcome. These data now provide a strong rationale to extensively test and compare neoadjuvant immunotherapy in humans.

Significance: We demonstrate the significantly greater therapeutic efficacy of neoadjuvant, compared with adjuvant, immunotherapies to eradicate distant metastases following primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior to and post surgery may provide a predictor of outcome. Cancer Discov; 6(12); 1382–99. ©2016 AACR.

See related commentary by Melero et al., p. 1312.

This article is highlighted in the In This Issue feature, p. 1293
Data from Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma
Authors: Mishra Anjali , La Perle Krista , Kwiatkowski Sonya , Sullivan Laura A. , Sams Gregory H. , Johns Jessica , Curphey Douglas P. , Wen Jing , McConnell Kathleen , Qi Jun , Wong Henry , Russo Giandomenico , Zhang Jianying , Marcucci Guido , Bradner James E. , Porcu Pierluigi , Caligiuri Michael A.
Published: March 2024

Abstract
Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage–dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15. Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.

Significance: To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986–1005. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 932
Data from Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy
Authors: Incio Joao , Liu Hao , Suboj Priya , Chin Shan M. , Chen Ivy X. , Pinter Matthias , Ng Mei R. , Nia Hadi T. , Grahovac Jelena , Kao Shannon , Babykutty Suboj , Huang Yuhui , Jung Keehoon , Rahbari Nuh N. , Han Xiaoxing , Chauhan Vikash P. , Martin John D. , Kahn Julia , Huang Peigen , Desphande Vikram , Michaelson James , Michelakos Theodoros P. , Ferrone Cristina R. , Soares Raquel , Boucher Yves , Fukumura Dai , Jain Rakesh K.
Published: March 2024

Abstract
It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.

Significance: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852–69. ©2016 AACR.

See related commentary by Bronte and Tortora, p. 821.

This article is highlighted in the In This Issue feature, p. 803
Data from CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas
Authors: Jiang Yanwen , Ortega-Molina Ana , Geng Huimin , Ying Hsia-Yuan , Hatzi Katerina , Parsa Sara , McNally Dylan , Wang Ling , Doane Ashley S. , Agirre Xabier , Teater Matt , Meydan Cem , Li Zhuoning , Poloway David , Wang Shenqiu , Ennishi Daisuke , Scott David W. , Stengel Kristy R. , Kranz Janice E. , Holson Edward , Sharma Sneh , Young James W. , Chu Chi-Shuen , Roeder Robert G. , Shaknovich Rita , Hiebert Scott W. , Gascoyne Randy D. , Tam Wayne , Elemento Olivier , Wendel Hans-Guido , Melnick Ari M.
Published: March 2024

Abstract
Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)–derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo. Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas.

Significance: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38–53. ©2016 AACR.

See related commentary by Höpken, p. 14.

This article is highlighted in the In This Issue feature, p. 1
Data from CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplified Genomic Regions
Authors: Munoz Diana M. , Cassiani Pamela J. , Li Li , Billy Eric , Korn Joshua M. , Jones Michael D. , Golji Javad , Ruddy David A. , Yu Kristine , McAllister Gregory , DeWeck Antoine , Abramowski Dorothee , Wan Jessica , Shirley Matthew D. , Neshat Sarah Y. , Rakiec Daniel , de Beaumont Rosalie , Weber Odile , Kauffmann Audrey , McDonald E. Robert , Keen Nicholas , Hofmann Francesco , Sellers William R. , Schmelzle Tobias , Stegmeier Frank , Schlabach Michael R.
Published: March 2024

Abstract
CRISPR/Cas9 has emerged as a powerful new tool to systematically probe gene function. We compared the performance of CRISPR to RNAi-based loss-of-function screens for the identification of cancer dependencies across multiple cancer cell lines. CRISPR dropout screens consistently identified more lethal genes than RNAi, implying that the identification of many cellular dependencies may require full gene inactivation. However, in two aneuploid cancer models, we found that all genes within highly amplified regions, including nonexpressed genes, scored as lethal by CRISPR, revealing an unanticipated class of false-positive hits. In addition, using a CRISPR tiling screen, we found that sgRNAs targeting essential domains generate the strongest lethality phenotypes and thus provide a strategy to rapidly define the protein domains required for cancer dependence. Collectively, these findings not only demonstrate the utility of CRISPR screens in the identification of cancer-essential genes, but also reveal the need to carefully control for false-positive results in chromosomally unstable cancer lines.

Significance: We show in this study that CRISPR-based screens have a significantly lower false-negative rate compared with RNAi-based screens, but have specific liabilities particularly in the interrogation of regions of genome amplification. Therefore, this study provides critical insights for applying CRISPR-based screens toward the systematic identification of new cancer targets. Cancer Discov; 6(8); 900–13. ©2016 AACR.

See related commentary by Sheel and Xue, p. 824.

See related article by Aguirre et al., p. 914.

This article is highlighted in the In This Issue feature, p. 803
Data from Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney
Authors: Mehra Rohit , Vats Pankaj , Cieslik Marcin , Cao Xuhong , Su Fengyun , Shukla Sudhanshu , Udager Aaron M. , Wang Rui , Pan Jincheng , Kasaian Katayoon , Lonigro Robert , Siddiqui Javed , Premkumar Kumpati , Palapattu Ganesh , Weizer Alon , Hafez Khaled S. , Wolf J. Stuart , Sangoi Ankur R. , Trpkov Kiril , Osunkoya Adeboye O. , Zhou Ming , Giannico Giovanna , McKenney Jesse K. , Dhanasekaran Saravana M. , Chinnaiyan Arul M.
Published: March 2024

Abstract
Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation.

Significance: MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258–66. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1197
Data from Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer
Authors: Carter Hannah , Marty Rachel , Hofree Matan , Gross Andrew M. , Jensen James , Fisch Kathleen M. , Wu Xingyu , DeBoever Christopher , Van Nostrand Eric L. , Song Yan , Wheeler Emily , Kreisberg Jason F. , Lippman Scott M. , Yeo Gene W. , Gutkind J. Silvio , Ideker Trey
Published: March 2024

Abstract
Recent studies have characterized the extensive somatic alterations that arise during cancer. However, the somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. Here, we analyze genomic data for 5,954 tumors to reveal and systematically validate 412 genetic interactions between germline polymorphisms and major somatic events, including tumor formation in specific tissues and alteration of specific cancer genes. Among germline–somatic interactions, we found germline variants in RBFOX1 that increased incidence of SF3B1 somatic mutation by 8-fold via functional alterations in RNA splicing. Similarly, 19p13.3 variants were associated with a 4-fold increased likelihood of somatic mutations in PTEN. In support of this association, we found that PTEN knockdown sensitizes the MTOR pathway to high expression of the 19p13.3 gene GNA11. Finally, we observed that stratifying patients by germline polymorphisms exposed distinct somatic mutation landscapes, implicating new cancer genes. This study creates a validated resource of inherited variants that govern where and how cancer develops, opening avenues for prevention research.

Significance: This study systematically identifies germline variants that directly affect tumor evolution, either by dramatically increasing alteration frequency of specific cancer genes or by influencing the site where a tumor develops. Cancer Discovery; 7(4); 410–23. ©2017 AACR.

See related commentary by Geeleher and Huang, p. 354.

This article is highlighted in the In This Issue feature, p. 339
Data from Autocrine Complement Inhibits IL10-Dependent T-cell–Mediated Antitumor Immunity to Promote Tumor Progression
Authors: Wang Yu , Sun Sheng-Nan , Liu Qing , Yu Yang-Yang , Guo Jian , Wang Kun , Xing Bao-Cai , Zheng Qing-Feng , Campa Michael J. , Patz Edward F. , Li Shi-You , He You-Wen
Published: March 2024

Abstract
In contrast to its inhibitory effects on many cells, IL10 activates CD8+ tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell– and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy.

Significance: Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti–PD-1 to enhance anti–PD-1 efficacy; a targeted IL10 delivery to CD8+ TILs using anti–PD-1–IL10 or anti-CTLA4–IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022–35. ©2016 AACR.

See related commentary by Peng et al., p. 953.

This article is highlighted in the In This Issue feature, p. 932
Data from Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists
Authors: Toy Weiyi , Weir Hazel , Razavi Pedram , Lawson Mandy , Goeppert Anne U. , Mazzola Anne Marie , Smith Aaron , Wilson Joanne , Morrow Christopher , Wong Wai Lin , De Stanchina Elisa , Carlson Kathryn E. , Martin Teresa S. , Uddin Sharmeen , Li Zhiqiang , Fanning Sean , Katzenellenbogen John A. , Greene Geoffrey , Baselga José , Chandarlapaty Sarat
Published: March 2024

Abstract
Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation of the receptor. The degree to which all recurrent mutants can drive estrogen-independent activities and reduced sensitivity to ER antagonists like fulvestrant is not established. In this report, we characterize the spectrum of ESR1 mutations from more than 900 patients. ESR1 mutations were detected in 10%, with D538G being the most frequent (36%), followed by Y537S (14%). Several novel, activating mutations were also detected (e.g., L469V, V422del, and Y537D). Although many mutations lead to constitutive activity and reduced sensitivity to ER antagonists, only select mutants such as Y537S caused a magnitude of change associated with fulvestrant resistance in vivo. Correspondingly, tumors driven by Y537S, but not D5358G, E380Q, or S463P, were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists, including AZD9496. These data point to a need for antagonists with optimal pharmacokinetic properties to realize clinical efficacy against certain ESR1 mutants.

Significance: A diversity of activating ESR1 mutations exist, only some of which confer resistance to existing ER antagonists that might be overcome by next-generation inhibitors such as AZD9496. Cancer Discov; 7(3); 277–87. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 235
Data from Synthetic Lethality in ATM-Deficient RAD50-Mutant Tumors Underlies Outlier Response to Cancer Therapy
Authors: Al-Ahmadie Hikmat , Iyer Gopa , Hohl Marcel , Asthana Saurabh , Inagaki Akiko , Schultz Nikolaus , Hanrahan Aphrothiti J. , Scott Sasinya N. , Brannon A. Rose , McDermott Gregory C. , Pirun Mono , Ostrovnaya Irina , Kim Philip , Socci Nicholas D. , Viale Agnes , Schwartz Gary K. , Reuter Victor , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Berger Michael F. , Petrini John H.J. , Solit David B. , Taylor Barry S.
Published: March 2024

Abstract
Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function.

Significance: Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer. Cancer Discov; 4(9); 1014–21. ©2014 AACR.

See related commentary by Peng et al., p. 988

This article is highlighted in the In This Issue feature, p. 973
Data from Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor–Positive Breast Cancer
Authors: Matissek Karina J. , Onozato Maristela L. , Sun Sheng , Zheng Zongli , Schultz Andrew , Lee Jesse , Patel Kristofer , Jerevall Piiha-Lotta , Saladi Srinivas Vinod , Macleay Allison , Tavallai Mehrad , Badovinac-Crnjevic Tanja , Barrios Carlos , Beşe Nuran , Chan Arlene , Chavarri-Guerra Yanin , Debiasi Marcio , Demirdögen Elif , Egeli Ünal , Gökgöz Sahsuvar , Gomez Henry , Liedke Pedro , Tasdelen Ismet , Tolunay Sahsine , Werutsky Gustavo , St. Louis Jessica , Horick Nora , Finkelstein Dianne M. , Le Long Phi , Bardia Aditya , Goss Paul E. , Sgroi Dennis C. , Iafrate A. John , Ellisen Leif W.
Published: March 2024

Abstract
We sought to uncover genetic drivers of hormone receptor–positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.

Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336–53. ©2017 AACR.

See related commentary by Natrajan et al., p. 272.

See related article by Liu et al., p. 354.

This article is highlighted in the In This Issue feature, p. 253
Data from Targeting the MTF2–MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy
Authors: Maganti Harinad B. , Jrade Hani , Cafariello Christopher , Manias Rothberg Janet L. , Porter Christopher J. , Yockell-Lelièvre Julien , Battaion Hannah L. , Khan Safwat T. , Howard Joel P. , Li Yuefeng , Grzybowski Adrian T. , Sabri Elham , Ruthenburg Alexander J. , Dilworth F. Jeffrey , Perkins Theodore J. , Sabloff Mitchell , Ito Caryn Y. , Stanford William L.
Published: March 2024

Abstract
Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that metal response element binding transcription factor 2/polycomblike 2 (MTF2/PCL2) plays a fundamental role in the polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2–PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2-deficient CD34+CD38− cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell-cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.

Significance: MTF2 deficiency predicts refractory AML at diagnosis. MTF2 represses MDM2 in hematopoietic cells and its loss in AML results in chemoresistance. Inhibiting p53 degradation by overexpressing MTF2 in vitro or by using MDM2 inhibitors in vivo sensitizes MTF2-deficient refractory AML cells to a standard induction-chemotherapy regimen. Cancer Discov; 8(11); 1376–89. ©2018 AACR.

See related commentary by Duy and Melnick, p. 1348.

This article is highlighted in the In This Issue feature, p. 1333
Data from Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers
Authors: Olsen Sarah Naomi , Wronski Ania , Castaño Zafira , Dake Benjamin , Malone Clare , De Raedt Thomas , Enos Miriam , DeRose Yoko S. , Zhou Wenhui , Guerra Stephanie , Loda Massimo , Welm Alana , Partridge Ann H. , McAllister Sandra S. , Kuperwasser Charlotte , Cichowski Karen
Published: March 2024

Abstract
Luminal breast cancers are typically estrogen receptor–positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

Significance: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202–17. ©2016 AACR.

See related commentary by Sears and Gray, p. 131.

This article is highlighted in the In This Issue feature, p. 115
Data from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
Authors: Jusakul Apinya , Cutcutache Ioana , Yong Chern Han , Lim Jing Quan , Huang Mi Ni , Padmanabhan Nisha , Nellore Vishwa , Kongpetch Sarinya , Ng Alvin Wei Tian , Ng Ley Moy , Choo Su Pin , Myint Swe Swe , Thanan Raynoo , Nagarajan Sanjanaa , Lim Weng Khong , Ng Cedric Chuan Young , Boot Arnoud , Liu Mo , Ong Choon Kiat , Rajasegaran Vikneswari , Lie Stefanus , Lim Alvin Soon Tiong , Lim Tse Hui , Tan Jing , Loh Jia Liang , McPherson John R. , Khuntikeo Narong , Bhudhisawasdi Vajaraphongsa , Yongvanit Puangrat , Wongkham Sopit , Totoki Yasushi , Nakamura Hiromi , Arai Yasuhito , Yamasaki Satoshi , Chow Pierce Kah-Hoe , Chung Alexander Yaw Fui , Ooi London Lucien Peng Jin , Lim Kiat Hon , Dima Simona , Duda Dan G. , Popescu Irinel , Broet Philippe , Hsieh Sen-Yung , Yu Ming-Chin , Scarpa Aldo , Lai Jiaming , Luo Di-Xian , Carvalho André Lopes , Vettore André Luiz , Rhee Hyungjin , Park Young Nyun , Alexandrov Ludmil B. , Gordân Raluca , Rozen Steven G. , Shibata Tatsuhiro , Pairojkul Chawalit , Teh Bin Tean , Tan Patrick
Published: March 2024

Abstract
Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters—fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′ untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein–DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores—mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.

Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116–35. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1047
Data from An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer
Authors: Hanker Ariella B. , Brewer Monica Red , Sheehan Jonathan H. , Koch James P. , Sliwoski Gregory R. , Nagy Rebecca , Lanman Richard , Berger Michael F. , Hyman David M. , Solit David B. , He Jie , Miller Vincent , Cutler Richard E. , Lalani Alshad S. , Cross Darren , Lovly Christine M. , Meiler Jens , Arteaga Carlos L.
Published: March 2024

Abstract
We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.

Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2-mutant breast cancer upon clinical progression on neratinib. We speculate that HER2T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575–85. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 539