ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

Jianfeng Shen, Yang Peng, Leizhen Wei, Wei Zhang, Lin Yang, Li Lan, Prabodh Kapoor, Zhenlin Ju, Qianxing Mo, Ie Ming Shih, Ivan P. Uray, Xiangwei Wu, Powel H. Brown, Xuetong Shen, Gordon B. Mills, Guang Peng

    Research output: Contribution to journalArticle

    148 Scopus citations

    Abstract

    UNLABELLED: ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.

    SIGNIFICANCE: ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.

    Original languageEnglish (US)
    Pages (from-to)752-767
    Number of pages16
    JournalCancer discovery
    Volume5
    Issue number7
    DOIs
    StatePublished - Jul 1 2015

    ASJC Scopus subject areas

    • Oncology

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  • Cite this

    Shen, J., Peng, Y., Wei, L., Zhang, W., Yang, L., Lan, L., Kapoor, P., Ju, Z., Mo, Q., Shih, I. M., Uray, I. P., Wu, X., Brown, P. H., Shen, X., Mills, G. B., & Peng, G. (2015). ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors. Cancer discovery, 5(7), 752-767. https://doi.org/10.1158/2159-8290.CD-14-0849