Abstract The mammalian SWI/SNF complexes (mSWI/SNF) regulate chromatin structure through ATP-dependent nucleosome remodeling and thereby control key cellular processes. Recent cancer genome studies have revealed a significant frequency of mutations in several components of the mSWI/SNF complexes including the catalytic subunit BRG1. Emerging evidence is supportive of tumor suppressor roles for mSWI/SNF subunits, yet the inactivating nature of these mutations presents a challenge for devising targeted therapeutic strategies against cancers harboring such mutations. In this study, we interrogated epigenetic cancer dependencies by screening a deep-coverage design (DeCoDe) shRNA library targeting the epigenome across a broad range of 50+ cancer cell lines. Strikingly, this unbiased screen revealed that silencing of the SWI/SNF ATPase subunit BRM/SMARCA2, selectively inhibits the proliferation of BRG1-deficient cancer cells. 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. Thus, targeting mSWI/SNF subunits that exhibit redundant activities to the residual mutated complexes may present a general strategy for SWI/SNF mutated cancers. Citation Format: Mariela Jaskelioff, Gregory Hoffman, Rami Rahal, Kay Xiang, Kristy Haas, Veronica Saenz-Vash, Huili Zhai, Nicholas Keen, Frank Stegmeier, Zainab Jagani. BRM/SMARCA2 is a critical synthetic lethal target in BRG1-deficient cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 444. doi:10.1158/1538-7445.AM2014-444