ARID1B is a specific vulnerability in ARID1A-mutant cancers

KC Helming, X Wang, BG Wilson, F Vazquez… - Nature medicine, 2014 - nature.com
KC Helming, X Wang, BG Wilson, F Vazquez, JR Haswell, HE Manchester, Y Kim…
Nature medicine, 2014nature.com
Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-
like), is frequently mutated across a variety of human cancers and also has bona fide tumor
suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A
mutation would have major relevance for human cancer. Here, using a broad screening
approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually
exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required …
Abstract
Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.
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