bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia
Authors: Zhu Li , Li Qin , Wong Stephen H.K. , Huang Min , Klein Brianna J. , Shen Jinfeng , Ikenouye Larissa , Onishi Masayuki , Schneidawind Dominik , Buechele Corina , Hansen Loren , Duque-Afonso Jesús , Zhu Fangfang , Martin Gloria Mas , Gozani Or , Majeti Ravindra , Kutateladze Tatiana G. , Cleary Michael L.
Published: March 2024

Abstract
Numerous studies in multiple systems support that histone H3 lysine 36 dimethylation (H3K36me2) is associated with transcriptional activation; however, the underlying mechanisms are not well defined. Here, we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, a mixed-lineage leukemia (MLL)–associated protein that colocalizes with MLL, ASH1L, and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely, KDM2A, an H3K36me2 demethylase and Polycomb group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies are the first to provide a basic mechanistic insight into epigenetic interactions wherein placement, interpretation, and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a novel target for therapeutic intervention.

Significance: Epigenetic regulators play vital roles in cancer pathogenesis and represent a new frontier in therapeutic targeting. Our studies provide basic mechanistic insight into the role of H3K36me2 in transcription activation and MLL leukemia pathogenesis and implicate ASH1L histone methyltransferase as a promising target for novel molecular therapy. Cancer Discov; 6(7); 770–83. ©2016 AACR.

See related commentary by Balbach and Orkin, p. 700.

This article is highlighted in the In This Issue feature, p. 681
Data from ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors
Authors: Shen Jianfeng , Peng Yang , Wei Leizhen , Zhang Wei , Yang Lin , Lan Li , Kapoor Prabodh , Ju Zhenlin , Mo Qianxing , Shih Ie-Ming , Uray Ivan P. , Wu Xiangwei , Brown Powel H. , Shen Xuetong , Mills Gordon B. , Peng Guang
Published: March 2024

Abstract
ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.

Significance:ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors. Cancer Discov; 5(7); 752–67. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 681
Data from Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
Authors: Kaneda Megan M. , Cappello Paola , Nguyen Abraham V. , Ralainirina Natacha , Hardamon Chanae R. , Foubert Philippe , Schmid Michael C. , Sun Ping , Mose Evangeline , Bouvet Michael , Lowy Andrew M. , Valasek Mark A. , Sasik Roman , Novelli Francesco , Hirsch Emilio , Varner Judith A.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a low 5-year survival rate, yet new immunotherapeutic modalities may offer hope for this and other intractable cancers. Here, we report that inhibitory targeting of PI3Kγ, a key macrophage lipid kinase, stimulates antitumor immune responses, leading to improved survival and responsiveness to standard-of-care chemotherapy in animal models of PDAC. PI3Kγ selectively drives immunosuppressive transcriptional programming in macrophages that inhibits adaptive immune responses and promotes tumor cell invasion and desmoplasia in PDAC. Blockade of PI3Kγ in PDAC-bearing mice reprograms tumor-associated macrophages to stimulate CD8+ T-cell–mediated tumor suppression and to inhibit tumor cell invasion, metastasis, and desmoplasia. These data indicate the central role that macrophage PI3Kγ plays in PDAC progression and demonstrate that pharmacologic inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.

Significance: We report here that PI3Kγ regulates macrophage transcriptional programming, leading to T-cell suppression, desmoplasia, and metastasis in pancreas adenocarcinoma. Genetic or pharmacologic inhibition of PI3Kγ restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy. PI3Kγ represents a new therapeutic immune target for pancreas cancer. Cancer Discov; 6(8); 870–85. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 803
Data from A Recurrent ERCC3 Truncating Mutation Confers Moderate Risk for Breast Cancer
Authors: Vijai Joseph , Topka Sabine , Villano Danylo , Ravichandran Vignesh , Maxwell Kara N. , Maria Ann , Thomas Tinu , Gaddam Pragna , Lincoln Anne , Kazzaz Sarah , Wenz Brandon , Carmi Shai , Schrader Kasmintan A. , Hart Steven N. , Lipkin Steve M. , Neuhausen Susan L. , Walsh Michael F. , Zhang Liying , Lejbkowicz Flavio , Rennert Hedy , Stadler Zsofia K. , Robson Mark , Weitzel Jeffrey N. , Daly Mark J. , Couch Fergus J. , Nathanson Katherine L. , Norton Larry , Rennert Gad , Offit Kenneth
Published: March 2024

Abstract
Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer–affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair–deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (ORBC = 1.53, ORER+ = 1.73), particularly for the estrogen receptor–positive subset (P < 0.007).

Significance: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267–75. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1197
Data from Chronic Myelogenous Leukemia– Initiating Cells Require Polycomb Group Protein EZH2
Authors: Xie Huafeng , Peng Cong , Huang Jialiang , Li Bin E. , Kim Woojin , Smith Elenoe C. , Fujiwara Yuko , Qi Jun , Cheloni Giulia , Das Partha P. , Nguyen Minh , Li Shaoguang , Bradner James E. , Orkin Stuart H.
Published: March 2024

Abstract
Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs and required for colony formation and survival and cell-cycle progression of CML cell lines. A critical role for EZH2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR–ABL1 mutational status, and extends survival. Expression of the EZH2 homolog EZH1 is reduced in EZH2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2 dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors.

Significance: This work defines EZH2 as a selective vulnerability for CML cells and their LICs, regardless of BCR–ABL1 mutational status. Our findings provide an experimental rationale for improving disease eradication through judicious use of EZH2 inhibitors within the context of standard-of-care TKI therapy. Cancer Discov; 6(11); 1237–47. ©2016 AACR.

See related article by Scott et al., p. 1248.

This article is highlighted in the In This Issue feature, p. 1197
Data from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial
Authors: Pearson Alex , Smyth Elizabeth , Babina Irina S. , Herrera-Abreu Maria Teresa , Tarazona Noelia , Peckitt Clare , Kilgour Elaine , Smith Neil R. , Geh Catherine , Rooney Claire , Cutts Ros , Campbell James , Ning Jian , Fenwick Kerry , Swain Amanda , Brown Gina , Chua Sue , Thomas Anne , Johnston Stephen R.D. , Ajaz Mazhar , Sumpter Katherine , Gillbanks Angela , Watkins David , Chau Ian , Popat Sanjay , Cunningham David , Turner Nicholas C.
Published: March 2024

Abstract
FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.

Significance: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838–51. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 803
Data from Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
Authors: Roberts Nicholas J. , Norris Alexis L. , Petersen Gloria M. , Bondy Melissa L. , Brand Randall , Gallinger Steven , Kurtz Robert C. , Olson Sara H. , Rustgi Anil K. , Schwartz Ann G. , Stoffel Elena , Syngal Sapna , Zogopoulos George , Ali Syed Z. , Axilbund Jennifer , Chaffee Kari G. , Chen Yun-Ching , Cote Michele L. , Childs Erica J. , Douville Christopher , Goes Fernando S. , Herman Joseph M. , Iacobuzio-Donahue Christine , Kramer Melissa , Makohon-Moore Alvin , McCombie Richard W. , McMahon K. Wyatt , Niknafs Noushin , Parla Jennifer , Pirooznia Mehdi , Potash James B. , Rhim Andrew D. , Smith Alyssa L. , Wang Yuxuan , Wolfgang Christopher L. , Wood Laura D. , Zandi Peter P. , Goggins Michael , Karchin Rachel , Eshleman James R. , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Hruban Ralph H. , Klein Alison P.
Published: March 2024

Abstract
Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types.

Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 109
Data from Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer
Authors: Russo Mariangela , Misale Sandra , Wei Ge , Siravegna Giulia , Crisafulli Giovanni , Lazzari Luca , Corti Giorgio , Rospo Giuseppe , Novara Luca , Mussolin Benedetta , Bartolini Alice , Cam Nicholas , Patel Roopal , Yan Shunqi , Shoemaker Robert , Wild Robert , Di Nicolantonio Federica , Bianchi Andrea Sartore , Li Gang , Siena Salvatore , Bardelli Alberto
Published: March 2024

Abstract
Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA–NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.

Significance: We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1); 36–44. ©2015 AACR.

See related commentary by Okimoto and Bivona, p. 14.

This article is highlighted in the In This Issue feature, p. 1
Data from Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting
Authors: Aguirre Andrew J. , Meyers Robin M. , Weir Barbara A. , Vazquez Francisca , Zhang Cheng-Zhong , Ben-David Uri , Cook April , Ha Gavin , Harrington William F. , Doshi Mihir B. , Kost-Alimova Maria , Gill Stanley , Xu Han , Ali Levi D. , Jiang Guozhi , Pantel Sasha , Lee Yenarae , Goodale Amy , Cherniack Andrew D. , Oh Coyin , Kryukov Gregory , Cowley Glenn S. , Garraway Levi A. , Stegmaier Kimberly , Roberts Charles W. , Golub Todd R. , Meyerson Matthew , Root David E. , Tsherniak Aviad , Hahn William C.
Published: March 2024

Abstract
The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased cell viability after genome editing. Within regions of copy-number gain, CRISPR/Cas9 targeting of both expressed and unexpressed genes, as well as intergenic loci, led to significantly decreased cell proliferation through induction of a G2 cell-cycle arrest. By examining single-guide RNAs that map to multiple genomic sites, we found that this cell response to CRISPR/Cas9 editing correlated strongly with the number of target loci. These observations indicate that genome targeting by CRISPR/Cas9 elicits a gene-independent antiproliferative cell response. This effect has important practical implications for the interpretation of CRISPR/Cas9 screening data and confounds the use of this technology for the identification of essential genes in amplified regions.

Significance: We found that the number of CRISPR/Cas9-induced DNA breaks dictates a gene-independent antiproliferative response in cells. These observations have practical implications for using CRISPR/Cas9 to interrogate cancer gene function and illustrate that cancer cells are highly sensitive to site-specific DNA damage, which may provide a path to novel therapeutic strategies. Cancer Discov; 6(8); 914–29. ©2016 AACR.

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

See related article by Munoz et al., p. 900.

This article is highlighted in the In This Issue feature, p. 803
Data from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia
Authors: Trinquand Amélie , dos Santos Nuno R. , Tran Quang Christine , Rocchetti Francesca , Zaniboni Benedetta , Belhocine Mohamed , Da Costa de Jesus Cindy , Lhermitte Ludovic , Tesio Melania , Dussiot Michael , Cosset François-Loïc , Verhoeyen Els , Pflumio Françoise , Ifrah Norbert , Dombret Hervé , Spicuglia Salvatore , Chatenoud Lucienne , Gross David-Alexandre , Hermine Olivier , Macintyre Elizabeth , Ghysdael Jacques , Asnafi Vahid
Published: March 2024

Abstract
Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ϵ chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.

Significance: T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specific TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. Cancer Discov; 6(9); 972–85. ©2016 AACR.

See related commentary by Lemonnier and Mak, p. 946.

This article is highlighted in the In This Issue feature, p. 932
Data from Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)
Authors: Drilon Alexander , Siena Salvatore , Ou Sai-Hong Ignatius , Patel Manish , Ahn Myung Ju , Lee Jeeyun , Bauer Todd M. , Farago Anna F. , Wheler Jennifer J. , Liu Stephen V. , Doebele Robert , Giannetta Laura , Cerea Giulio , Marrapese Giovanna , Schirru Michele , Amatu Alessio , Bencardino Katia , Palmeri Laura , Sartore-Bianchi Andrea , Vanzulli Angelo , Cresta Sara , Damian Silvia , Duca Matteo , Ardini Elena , Li Gang , Christiansen Jason , Kowalski Karey , Johnson Ann D. , Patel Rupal , Luo David , Chow-Maneval Edna , Hornby Zachary , Multani Pratik S. , Shaw Alice T. , De Braud Filippo G.
Published: March 2024

Abstract
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non–small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1–NTRK1-rearranged lung cancer.

Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400–9. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 339
Data from RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors
Authors: Cheng Haiying , Zou Yiyu , Ross Jeffrey S. , Wang Kai , Liu Xuewen , Halmos Balazs , Ali Siraj M. , Liu Huijie , Verma Amit , Montagna Cristina , Chachoua Abraham , Goel Sanjay , Schwartz Edward L. , Zhu Changcheng , Shan Jidong , Yu Yiting , Gritsman Kira , Yelensky Roman , Lipson Doron , Otto Geoff , Hawryluk Matthew , Stephens Philip J. , Miller Vincent A. , Piperdi Bilal , Perez-Soler Roman
Published: March 2024

Abstract
We identified amplification of RICTOR, a key component of the mTOR complex 2 (mTORC2), as the sole actionable genomic alteration in an 18-year-old never-smoker with lung adenocarcinoma. Amplification of RICTOR occurs in 13% of lung cancers (1,016 cases) in The Cancer Genome Atlas and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTORC1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared with other agents targeting the PI3K–AKT–mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTORC1/2 inhibitors was observed. The index patient has been treated with mTORC1/2 inhibitors that led to tumor stabilization for more than 18 months.

Significance:RICTOR amplification may define a novel and unique molecular subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov; 5(12); 1262–70. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1225
Data from Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage–Derived VEGFA
Authors: Harney Allison S. , Arwert Esther N. , Entenberg David , Wang Yarong , Guo Peng , Qian Bin-Zhi , Oktay Maja H. , Pollard Jeffrey W. , Jones Joan G. , Condeelis John S.
Published: March 2024

Abstract
Dissemination of tumor cells is an essential step in metastasis. Direct contact between a macrophage, mammalian-enabled (MENA)–overexpressing tumor cell, and endothelial cell [Tumor MicroEnvironment of Metastasis (TMEM)] correlates with metastasis in breast cancer patients. Here we show, using intravital high-resolution two-photon microscopy, that transient vascular permeability and tumor cell intravasation occur simultaneously and exclusively at TMEM. The hyperpermeable nature of tumor vasculature is described as spatially and temporally heterogeneous. Using real-time imaging, we observed that vascular permeability is transient, restricted to the TMEM, and required for tumor cell dissemination. VEGFA signaling from TIE2hi TMEM macrophages causes local loss of vascular junctions, transient vascular permeability, and tumor cell intravasation, demonstrating a role for the TMEM within the primary mammary tumor. These data provide insight into the mechanism of tumor cell intravasation and vascular permeability in breast cancer, explaining the value of TMEM density as a predictor of distant metastatic recurrence in patients.

Significance: Tumor vasculature is abnormal with increased permeability. Here, we show that VEGFA signaling from TIE2hi TMEM macrophages results in local, transient vascular permeability and tumor cell intravasation. These data provide evidence for the mechanism underlying the association of TMEM with distant metastatic recurrence, offering a rationale for therapies targeting TMEM. Cancer Discov; 5(9); 932–43. ©2015 AACR.

See related commentary by Kadioglu and De Palma, p. 906.

This article is highlighted in the In This Issue feature, p. 893
Data from The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function
Authors: Wan Lixin , Chen Ming , Cao Juxiang , Dai Xiangpeng , Yin Qing , Zhang Jinfang , Song Su-Jung , Lu Ying , Liu Jing , Inuzuka Hiroyuki , Katon Jesse M. , Berry Kelsey , Fung Jacqueline , Ng Christopher , Liu Pengda , Song Min Sup , Xue Lian , Bronson Roderick T. , Kirschner Marc W. , Cui Rutao , Pandolfi Pier Paolo , Wei Wenyi
Published: March 2024

Abstract
BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APCFZR1, APCFZR1 earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization. Moreover, we identified FZR1 as a direct target of ERK and CYCLIN D1/CDK4 kinases. Phosphorylation of FZR1 inhibits APCFZR1, leading to elevation of a cohort of oncogenic APCFZR1 substrates to facilitate melanomagenesis. Importantly, CDK4 and/or BRAF/MEK inhibitors restore APCFZR1 E3 ligase activity, which might be critical for their clinical effects. Furthermore, FZR1 depletion cooperates with AKT hyperactivation to transform primary melanocytes, whereas genetic ablation of Fzr1 synergizes with Pten loss, leading to aberrant coactivation of BRAF/ERK and AKT signaling in mice. Our findings therefore reveal a reciprocal suppression mechanism between FZR1 and BRAF in controlling tumorigenesis.

Significance: FZR1 inhibits BRAF oncogenic functions via both APC-dependent proteolysis and APC-independent disruption of BRAF dimers, whereas hyperactivated ERK and CDK4 reciprocally suppress APCFZR1 E3 ligase activity. Aberrancies in this newly defined signaling network might account for BRAF hyperactivation in human cancers, suggesting that targeting CYCLIN D1/CDK4, alone or in combination with BRAF/MEK inhibition, can be an effective anti-melanoma therapy. Cancer Discov; 7(4); 424–41. ©2017 AACR.

See related commentary by Zhang and Bollag, p. 356.

This article is highlighted in the In This Issue feature, p. 339
Data from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma
Authors: Saha Supriya K. , Gordan John D. , Kleinstiver Benjamin P. , Vu Phuong , Najem Mortada S. , Yeo Jia-Chi , Shi Lei , Kato Yasutaka , Levin Rebecca S. , Webber James T. , Damon Leah J. , Egan Regina K. , Greninger Patricia , McDermott Ultan , Garnett Mathew J. , Jenkins Roger L. , Rieger-Christ Kimberly M. , Sullivan Travis B. , Hezel Aram F. , Liss Andrew S. , Mizukami Yusuke , Goyal Lipika , Ferrone Cristina R. , Zhu Andrew X. , Joung J. Keith , Shokat Kevan M. , Benes Cyril H. , Bardeesy Nabeel
Published: March 2024

Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant “gatekeeper” mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness.

Significance: IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. Cancer Discov; 6(7); 727–39. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 681
Data from Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance
Authors: Jeong Youngtae , Hoang Ngoc T. , Lovejoy Alexander , Stehr Henning , Newman Aaron M. , Gentles Andrew J. , Kong William , Truong Diana , Martin Shanique , Chaudhuri Aadel , Heiser Diane , Zhou Li , Say Carmen , Carter Justin N. , Hiniker Susan M. , Loo Billy W. , West Robert B. , Beachy Philip , Alizadeh Ash A. , Diehn Maximilian
Published: March 2024

Abstract
Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non–small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.

Significance: We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86–101. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 “Gatekeeper” F691L Mutation with PLX3397
Authors: Smith Catherine C. , Zhang Chao , Lin Kimberly C. , Lasater Elisabeth A. , Zhang Ying , Massi Evan , Damon Lauren E. , Pendleton Matthew , Bashir Ali , Sebra Robert , Perl Alexander , Kasarskis Andrew , Shellooe Rafe , Tsang Garson , Carias Heidi , Powell Ben , Burton Elizabeth A. , Matusow Bernice , Zhang Jiazhong , Spevak Wayne , Ibrahim Prabha N. , Le Mai H. , Hsu Henry H. , Habets Gaston , West Brian L. , Bollag Gideon , Shah Neil P.
Published: March 2024

Abstract
Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase “gatekeeper” residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation–mediated resistance are incompletely understood. We report the first cocrystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position.

Significance: We report the first cocrystal structure of FLT3 with a kinase inhibitor, elucidating the structural mechanism of resistance due to the gatekeeper F691L mutation. PLX3397 is a novel FLT3 inhibitor with in vitro activity against this mutation but is vulnerable to kinase domain mutations in the FLT3 activation loop. Cancer Discov; 5(6); 668–79. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 565
Data from Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State
Authors: Patricelli Matthew P. , Janes Matthew R. , Li Lian-Sheng , Hansen Rasmus , Peters Ulf , Kessler Linda V. , Chen Yuching , Kucharski Jeff M. , Feng Jun , Ely Tess , Chen Jeffrey H. , Firdaus Sarah J. , Babbar Anjali , Ren Pingda , Liu Yi
Published: March 2024

Abstract
KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRASG12C that inhibits mutant KRAS–driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry–based assay for assessing KRAS activation status, we show that the nucleotide state of KRASG12C is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRASG12C mutation generates a “hyperexcitable” rather than a “statically active” state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics.

Significance: A cell-active, mutant-specific, covalent inhibitor of KRASG12C is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRASG12C oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state. Cancer Discov; 6(3); 316–29. ©2016 AACR.

See related commentary by Westover et al., p. 233.

This article is highlighted in the In This Issue feature, p. 217
Data from LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern
Authors: Sun Tian-Tian , He Jie , Liang Qian , Ren Lin-Lin , Yan Ting-Ting , Yu Ta-Chung , Tang Jia-Yin , Bao Yu-Jie , Hu Ye , Lin Yanwei , Sun Danfeng , Chen Ying-Xuan , Hong Jie , Chen Haoyan , Zou Weiping , Fang Jing-Yuan
Published: March 2024

Abstract
Long noncoding RNAs (lncRNA) play a role in carcinogenesis. However, the function of lncRNAs in human gastric cancer remains largely unknown. In this study, we identified a novel lncRNA, GClnc1, which was upregulated and associated with tumorigenesis, tumor size, metastasis, and poor prognosis in gastric cancer. GClnc1 affected gastric cancer cell proliferation, invasiveness, and metastasis in multiple gastric cancer models. Mechanistically, GClnc1 bound WDR5 (a key component of histone methyltransferase complex) and KAT2A histone acetyltransferase, acted as a modular scaffold of WDR5 and KAT2A complexes, coordinated their localization, specified the histone modification pattern on the target genes, including SOD2, and consequently altered gastric cancer cell biology. Thus, GClnc1 is mechanistically, functionally, and clinically oncogenic in gastric cancer. Targeting GClnc1 and its pathway may be meaningful for treating patients with gastric cancer.

Significance: This report documents a novel lncRNA, GClnc1, which may act as a scaffold to recruit the WDR5 and KAT2A complex and modify the transcription of target genes. This study reveals that GClnc1 is an oncogenic lncRNA in human gastric cancer. Cancer Discov; 6(7); 784–801. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 681
Data from Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma
Authors: Qamra Aditi , Xing Manjie , Padmanabhan Nisha , Kwok Jeffrey Jun Ting , Zhang Shenli , Xu Chang , Leong Yan Shan , Lee Lim Ai Ping , Tang Qianqao , Ooi Wen Fong , Suling Lin Joyce , Nandi Tannistha , Yao Xiaosai , Ong Xuewen , Lee Minghui , Tay Su Ting , Keng Angie Tan Lay , Gondo Santoso Erna , Ng Cedric Chuan Young , Ng Alvin , Jusakul Apinya , Smoot Duane , Ashktorab Hassan , Rha Sun Young , Yeoh Khay Guan , Peng Yong Wei , Chow Pierce K.H. , Chan Weng Hoong , Ong Hock Soo , Soo Khee Chee , Kim Kyoung-Mee , Wong Wai Keong , Rozen Steven G. , Teh Bin Tean , Kappei Dennis , Lee Jeeyun , Connolly John , Tan Patrick
Published: March 2024

Abstract
Promoter elements play important roles in isoform and cell type–specific expression. We surveyed the epigenomic promoter landscape of gastric adenocarcinoma, analyzing 110 chromatin profiles (H3K4me3, H3K4me1, H3K27ac) of primary gastric cancers, gastric cancer lines, and nonmalignant gastric tissues. We identified nearly 2,000 promoter alterations (somatic promoters), many deregulated in various epithelial malignancies and mapping frequently to alternative promoters within the same gene, generating potential pro-oncogenic isoforms (RASA3). Somatic promoter–associated N-terminal peptides displaying relative depletion in tumors exhibited high-affinity MHC binding predictions and elicited potent T-cell responses in vitro, suggesting a mechanism for reducing tumor antigenicity. In multiple patient cohorts, gastric cancers with high somatic promoter usage also displayed reduced T-cell cytolytic marker expression. Somatic promoters are enriched in PRC2 occupancy, display sensitivity to EZH2 therapeutic inhibition, and are associated with novel cancer-associated transcripts. By generating tumor-specific isoforms and decreasing tumor antigenicity, epigenomic promoter alterations may thus drive intrinsic tumorigenesis and also allow nascent cancers to evade host immunity.

Significance: We apply epigenomic profiling to demarcate the promoter landscape of gastric cancer. Many tumor-specific promoters activate different promoters in the same gene, some generating pro-oncogenic isoforms. Tumor-specific promoters also reduce tumor antigenicity by causing relative depletion of immunogenic peptides, contributing to cancer immunoediting and allowing tumors to evade host immune attack. Cancer Discov; 7(6); 630–51. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 539
Data from Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition
Authors: Gil Del Alcazar Carlos R. , Huh Sung Jin , Ekram Muhammad B. , Trinh Anne , Liu Lin L. , Beca Francisco , Zi Xiaoyuan , Kwak Minsuk , Bergholtz Helga , Su Ying , Ding Lina , Russnes Hege G. , Richardson Andrea L. , Babski Kirsten , Min Hui Kim Elizabeth , McDonnell Charles H. , Wagner Jon , Rowberry Ron , Freeman Gordon J. , Dillon Deborah , Sorlie Therese , Coussens Lisa M. , Garber Judy E. , Fan Rong , Bobolis Kristie , Allred D. Craig , Jeong Joon , Park So Yeon , Michor Franziska , Polyak Kornelia
Published: March 2024

Abstract
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.

Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098–115. ©2017 AACR.

See related commentary by Speiser and Verdeil, p. 1062.

This article is highlighted in the In This Issue feature, p. 1047
Data from Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition
Authors: Jia Deshui , Augert Arnaud , Kim Dong-Wook , Eastwood Emily , Wu Nan , Ibrahim Ali H. , Kim Kee-Beom , Dunn Colin T. , Pillai Smitha P.S. , Gazdar Adi F. , Bolouri Hamid , Park Kwon-Sik , MacPherson David
Published: March 2024

Abstract
CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, whereas suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo. Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy.

Significance: Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in Crebbp-deleted tumors. These data provide a rationale for selectively treating CREBBP-mutant SCLC with HDAC inhibitors. Cancer Discov; 8(11); 1422–37. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1333
Data from Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma
Authors: Kalaora Shelly , Wolf Yochai , Feferman Tali , Barnea Eilon , Greenstein Erez , Reshef Dan , Tirosh Itay , Reuben Alexandre , Patkar Sushant , Levy Ronen , Quinkhardt Juliane , Omokoko Tana , Qutob Nouar , Golani Ofra , Zhang Jianhua , Mao Xizeng , Song Xingzhi , Bernatchez Chantale , Haymaker Cara , Forget Marie-Andrée , Creasy Caitlin , Greenberg Polina , Carter Brett W. , Cooper Zachary A. , Rosenberg Steven A. , Lotem Michal , Sahin Ugur , Shakhar Guy , Ruppin Eytan , Wargo Jennifer A. , Friedman Nir , Admon Arie , Samuels Yardena
Published: March 2024

Abstract
The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies.

Significance: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy. Cancer Discov; 8(11); 1366–75. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1333