Abstract LB-126: ARID1B is a specific vulnerability in ARID1A-mutant cancers

Abstract

Abstract Cancer genome sequencing efforts have revealed that ARID1A is frequently mutated in many types of cancer. Inactivating mutations occur in 45% of ovarian clear cell and endometrioid carcinomas, 19% of gastric cancers, 19% of bladder cancers, 14% of hepatocellular cancers, 12% of melanomas, and less frequently in colorectal, lung, breast and pancreatic cancers. ARID1A has also been validated as having bona fide tumor suppressor properties. Consequently, identification of specific vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. We therefore performed a systematic search for genetic vulnerabilities created by ARID1A mutation. Out of 9000+ genes screened, ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, was the number one gene preferentially required in ARID1A-mutant cancer cells. In validation studies, we find that knockdown of ARID1B indeed specifically impairs the proliferation of ARID1A-mutant cancer cell lines. Mechanistically, we show that loss of ARID1B in ARID1A-mutant cancer cell lines destabilizes the SWI/SNF complex and results in dissociation of the catalytic ATPase subunit SMARCA4. We further show that this finding also holds true in primary murine fibroblasts genetically engineered conditional for ARID1A. Our findings demonstrate that cancer cell lines harboring mutations in ARID1A are specifically dependent upon ARID1B and provide insight into the structural role of ARID1A/B in the SWI/SNF complex. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that all ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. These results also indicate that ARID1B could be considered a potential therapeutic target for the wide variety of ARID1A-mutant human cancers. [K.H. and X.W contributed equally to this work.] Citation Format: Katherine Helming, Xiaofeng Wang, Boris Wilson, Francisca Vazquez, Jeffrey Haswell, Haley Manchester, Youngha Kim, Gregory V. Kryukov, Mahmoud Ghandi, Andrew J. Aguirre, Zainab Jagani, Zhong Wang, Levi Garraway, William Hahn, Charles Roberts. ARID1B is a specific vulnerability in ARID1A-mutant 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 LB-126. doi:10.1158/1538-7445.AM2014-LB-126