{"doi":"10.1172/jci130445","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'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.","journal":"Journal of Clinical Investigation","year":2020,"id":54275,"datarank":2.8552359209878437,"base_score":4.68213122712422,"endowment":4.68213122712422,"self_citation_contribution":0.7023196840686331,"citation_network_contribution":2.1529162369192107,"self_endowment_contribution":0.7023196840686331,"citer_contribution":2.1529162369192107,"corpus_percentile":null,"corpus_rank":null,"citation_count":107,"citer_count":107,"citers_with_citation_signal":91,"citers_with_endowment":91,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9636,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":278423,"name":"Lin Yang","orcid":"0000-0001-8201-0584","position":1,"is_corresponding":false},{"id":278424,"name":"Chen Wang","orcid":"0009-0000-4662-6226","position":2,"is_corresponding":false},{"id":264018,"name":"Zhao Wei","orcid":"0000-0001-5103-3871","position":3,"is_corresponding":false},{"id":69710,"name":"Zhenlin Ju","orcid":"0000-0001-7496-7909","position":4,"is_corresponding":false},{"id":278425,"name":"Wei Zhang","orcid":"0000-0001-9474-9351","position":5,"is_corresponding":false},{"id":277802,"name":"Jianfeng Shen","orcid":"0000-0001-9779-6225","position":6,"is_corresponding":false},{"id":278426,"name":"Yang Peng","orcid":"0000-0002-0630-9506","position":7,"is_corresponding":false},{"id":278427,"name":"Clemens An","orcid":"0000-0001-5197-7426","position":8,"is_corresponding":false},{"id":278428,"name":"Yen Luu","orcid":"0000-0002-5198-1449","position":9,"is_corresponding":false},{"id":265913,"name":"Shumei Song","orcid":"0000-0002-8128-6287","position":10,"is_corresponding":false},{"id":89413,"name":"Timothy A. Yap","orcid":"0000-0002-2154-3309","position":11,"is_corresponding":false},{"id":69924,"name":"Jaffer A. Ajani","orcid":"0000-0001-9946-0629","position":12,"is_corresponding":false},{"id":13817,"name":"Gordon B. Mills","orcid":"0000-0002-0144-9614","position":13,"is_corresponding":false},{"id":52461,"name":"Xuetong Shen","orcid":null,"position":14,"is_corresponding":false},{"id":277815,"name":"Guang Peng","orcid":"0000-0002-4392-1497","position":15,"is_corresponding":false},{"id":278422,"name":"Lulu Wang","orcid":"0000-0001-8402-5616","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:03:43.037640Z","pmid":"33016929","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}