@article{d6f293a8f43b4b45adb201af19c6362d,
title = "Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors",
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{\textquoteright}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.",
author = "Lulu Wang and Lin Yang and Chen Wang and Wei Zhao and Zhenlin Ju and Wei Zhang and Jianfeng Shen and Yang Peng and Clemens An and Luu, {Yen T.} and Shumei Song and Yap, {Timothy A.} and Ajani, {Jaffer A.} and Mills, {Gordon B} and Xuetong Shen and Guang Peng",
note = "Funding Information: We thank Shiaw-Yih Lin for critically reviewing our manuscript. This research was supported by NCI Cancer Center Support grant CA016672 to The University of Texas MD Anderson Cancer Center; NIH R01 grant CA181663 to GP; Cancer Prevention and Research Institute of Texas grant RP160242 to XS and GP; Ovarian Cancer Research Foundation grants 5P50 CA217685-02, 7U01 CA217842-03, 5P50 CA098258-13, and 545152; Adelson Medical Research Foundation grant 04-7023433 to GBM; and a Developmental Research Program grant to GP under the MD Anderson Uterine Cancer Specialized Programs of Research Excellence (SPORE) in Uterine Cancer (NCI grant P50CA098258). Funding Information: Authorship note: LW, LY, and CW contributed equally to this work. GP and XS are co–corresponding authors. Conflict of interest: GBM has received sponsored research support from Nanostring Center of Excellence, Ionis (provision of tool compounds) and clinical trials support from AstraZeneca, Genentech, GSK, and Eli Lilly; he has ownership interest in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda; he is a consultant/advisory board member of AstraZeneca, Chrysallis Biotechnology, ImmunoMet, Ionis, Lilly,PDX Pharmaceuticals, SignalChem Lifesciences, Symphogen, Tarveda, Turbine, and Zen-talis Pharmaceuticals; he has licensed technology for a homologous recombination deficiency assay to Myriad Genetics and for digital spatial profiling to Nanostring. TAY has received sponsored research support from AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius/Formation Biologics, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Sanofi, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals; he is a consultant/advisory board member of Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Kyn Therapeutics, Merck, Pfizer, Roche, Seattle Genetics, and Zai Labs. GP has received sponsored research support from Pfizer. Copyright: {\textcopyright} 2020, American Society for Clinical Investigation. Submitted: May 21, 2019; Accepted: July 9, 2020; Published: October 5, 2020. Reference information: J Clin Invest. 2020;130(11):5951–5966. https://doi.org/10.1172/JCI130445. Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = nov,
day = "2",
doi = "10.1172/JCI130445",
language = "English (US)",
volume = "130",
pages = "5951--5966",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",
}