Helming, Katherine C.Wang, XiaofengWilson, Boris G.Vazquez, FranciscaHaswell, JeffreyManchester, HaleyKim, YounghaKryukov, Gregory V.Ghandi, MahmoudAguirre, AndrewJagani, ZainabWang, ZhongGarraway, Levi A.Hahn, William C.Roberts, Charles W. M.2014-10-012014Helming, K. C., X. Wang, B. G. Wilson, F. Vazquez, J. R. Haswell, H. E. Manchester, Y. Kim, et al. 2014. “ARID1B is a specific vulnerability in ARID1A-mutant cancers.” Nature medicine 20 (3): 251-254. doi:10.1038/nm.3480. http://dx.doi.org/10.1038/nm.3480.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:12987227Summary Recent studies have revealed that ARID1A is frequently mutated across a wide 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, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one 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. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that 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. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.en-USJournal Article2014-10-0110.1038/nm.3480