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A functional screen of the epigenome identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

Hoffman, Gregory, Rahal, Rami, Buxton, Frank, Mcallister, Gregory, Xiang, Xiaoqin, Frias, Elizabeth, Huber, Janina, Lindeman, Alicia, Chen, Dongshu, Bagdasarian, Linda, Romero, Rodrigo, Ramadan, Nadire, Phadke, Tanushree, Haas, Kristy, Jaskelioff, Mariela, Wilson, Boris, Meyer, Matthew, Saenz-Vash, Veronica, Zhai, Huili, Mclaughlin, Margaret, Charles, Roberts, Myer, Vic, Porter, Jeffrey, Keen, Nicholas, Mickanin, Craig, Stegmeier, Frank and Jagani, Zainab (2013) A functional screen of the epigenome identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Molecular Cancer Therapeutics, 12 (11). ISSN 15357163


Epigenetic dysregulation is an emerging hallmark of cancers, and the identification of recurrent somatic mutations in chromatin regulators implies a causal role for altered chromatin states in tumorigenesis. As the majority of epigenetic mutations are inactivating and thus do not present directly druggable targets, we reasoned that these mutations may alter the epigenomic state of cancer cells and thereby expose novel epigenetic vulnerabilities. To systematically search for epigenetic synthetic lethal interactions, we performed a deep coverage pooled shRNA screen across a large collection of cancer cell lines using a library targeting a diverse set of epigenetic regulators. Strikingly, this unbiased screen revealed that silencing of the SWI/SNF ATPase subunit BRM/SMARCA2, selectively inhibits the proliferation of BRG1-deficient cancer cells. The mammalian SWI/SNF complexes (mSWI/SNF) regulate chromatin structure through ATP-dependent nucleosome remodeling. Recent cancer genome studies have revealed a significant frequency of mutations in several components of the mSWI/SNF complexes including loss of the catalytic subunit BRG1 in non-small cell lung cancers. Our studies reveal that BRM knockdown selectively induced cell cycle arrest in BRG1-mutant cancer cells and significantly impaired the growth of BRG1-mutant lung tumor xenografts. BRM is the paralog of BRG1, suggesting a model in which mSWI/SNF mutations lead to a hypomorphic complex that promotes tumorigenesis but cannot tolerate complete inactivation. Therefore, our studies present BRM as an attractive therapeutic target in BRG1-mutant cancers.

Item Type: Article
Date Deposited: 29 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46


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