ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression3, which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.
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This research was supported by NCI Cancer Center Support Grant CA016672 to The University of Texas MD Anderson Cancer Center, Department of Defense grant OC140431, NIH R01 grant CA181663 to G.P., Cancer Prevention and Research Institute of Texas grant RP160242 to X.S. and G.P., NIH R01 grant GM093104 to X.S, and NIH P01 grant CA092584 to Z.D.N.
G.B.M. has received sponsored research support from Abbvie, AstraZeneca, Critical Outcomes Technology, Horizon Diagnostics, Illumina, Immunomet, Ionis, Karus Therapeutics, Nanostring, Pfizer, Takeda/Millennium Pharmaceuticals, and Tesaro; has ownership interest in Catena Pharmaceuticals, PTV Ventures, and Spindle Top Ventures; and is a consultant/advisory board member of AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Medimmune, Nuevolution, Pfizer, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda. G.P. has received sponsored research support from Pifzer. No potential conflicts of interest were disclosed by the other authors.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–14
ARID1A mutation rate across cancer types
MS peptides in Vector- and ARID1A-expressing 293T cells
Ingenuity pathway analysis of ARID1A-interacting proteins
Mutation load in tumors with wild-type or mutant ARID1A, BRG1
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Shen, J., Ju, Z., Zhao, W. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 24, 556–562 (2018). https://doi.org/10.1038/s41591-018-0012-z
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