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ARID1B is a specific vulnerability in ARID1A-mutant cancers.
Nat. Med..02 23, 2014;20(3):251-4.
Helming KC, Wang X, Wilson BG, Vazquez F, Haswell JR, Manchester HE, Kim Y, Kryukov GV, Ghandi M, Aguirre AJ, Jagani Z, Wang Z, Garraway LA, Hahn WC, Roberts CW.
1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.  Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.  Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.  Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.  Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
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.