Journal
NATURE MEDICINE
Volume 20, Issue 3, Pages 251-254Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3480
Keywords
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Funding
- David Abraham Foundation
- Rally Foundation
- St. Baldrick's Foundation
- Pablove Foundation
- US National Institutes of Health [R01HL109054, R01CA172152, R01CA113794]
- U01 NCI Mouse Models of Cancer Consortium Award
- Garrett B. Smith Foundation
- Miles for Mary
- Cure AT/RT Now foundation
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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 ARID14-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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