Abstract
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.
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Acknowledgements
We thank Ping Lu for technical assistance with the setup of the sucrose sedimentation assay. X.W. was supported by a post-doctoral fellowship from David Abraham Foundation and Rally Foundation and a research grant from St. Baldrick's Foundation. B.G.W. was supported by a Childhood Cancer Research Grant from the Pablove Foundation. Z.W. is supported by US National Institutes of Health grant R01HL109054. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.) and R01CA113794 (C.W.M.R.) and a U01 NCI Mouse Models of Cancer Consortium Award (C.W.M.R.). The Garrett B. Smith Foundation, Miles for Mary and the Cure AT/RT Now foundation (C.W.M.R.) provided additional support.
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C.W.M.R. directed the study. K.C.H. and X.W. designed and performed experiments. J.R.H. and H.E.M. performed experiments. C.W.M.R., K.C.H., X.W., B.G.W., J.R.H., H.E.M. and Z.J. analyzed and interpreted the data. K.C.H., B.G.W., F.V. and A.J.A. analyzed Project Achilles data. G.V.K., M.G. and L.A.G. provided and analyzed sequencing data. Z.W. provided Arid1a-conditional mice, intellectual contribution and useful discussion. Y.K. established the Arid1a-conditional mouse strain. W.C.H. directs the Achilles Project, provided reagents, helped interpret Achilles data and edited the manuscript. C.W.M.R., K.C.H. and X.W. wrote the manuscript.
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Helming, K., Wang, X., Wilson, B. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med 20, 251–254 (2014). https://doi.org/10.1038/nm.3480
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DOI: https://doi.org/10.1038/nm.3480
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