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Nat Med DOI:10.1038/nm.3480

ARID1B is a specific vulnerability in ARID1A-mutant cancers.

Publication TypeJournal Article
Year of Publication2014
AuthorsHelming, 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, CWM
JournalNat Med
Date Published2014 Mar
KeywordsAlleles, Animals, Cell Line, Cell Nucleus, Cell Proliferation, Chromatin, DNA-Binding Proteins, False Positive Reactions, Fibroblasts, Gene Expression Regulation, Neoplastic, Gene Silencing, HEK293 Cells, Humans, Mice, Mutation, Neoplasms, Nuclear Proteins, RNA, Small Interfering, Time Factors, Transcription Factors

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.


Alternate JournalNat. Med.
PubMed ID24562383
PubMed Central IDPMC3954704
Grant ListU01 CA105423 / CA / NCI NIH HHS / United States
R01CA172152 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01 CA113794 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
R01 HL109054 / HL / NHLBI NIH HHS / United States
R01HL109054 / HL / NHLBI NIH HHS / United States
R01 CA172152 / CA / NCI NIH HHS / United States
R01CA113794 / CA / NCI NIH HHS / United States