ARID1B is a specific vulnerability in ARID1A-mutant cancers

作者：Helming Katherine C; Wang Xiaofeng; Wilson Boris G; Vazquez Francisca; Haswell Jeffrey R; Manchester Haley E; Kim Youngha; Kryukov Gregory V; Ghandi Mahmoud; Aguirre Andrew J; Jagani Zainab; Wang Zhong; Garraway Levi A; Hahn William C; Roberts Charles W M^*

来源：Nature Medicine, 2014, 20(3): 251-254.

DOI：10.1038/nm.3480

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.

• 出版日期2014-3