Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors

Lulu Wang, Lin Yang, Chen Wang, Wei Zhao, Zhenlin Ju, Wei Zhang, Jianfeng Shen, Yang Peng, Clemens An, Yen T. Luu, Shumei Song, Timothy A. Yap, Jaffer A. Ajani, Gordon B. Mills, Xuetong Shen, Guang Peng

    Research output: Contribution to journalArticlepeer-review

    Abstract

    ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A’s targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell–intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.

    Original languageEnglish (US)
    Pages (from-to)5951-5966
    Number of pages16
    JournalJournal of Clinical Investigation
    Volume130
    Issue number11
    DOIs
    StatePublished - Nov 2 2020

    ASJC Scopus subject areas

    • Medicine(all)

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