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ATR inhibition in SCLC activates the stimulator of interferon genes (STING)\u2013mediated interferon signaling, recruits T cells, and augments the antitumor immune response of programmed death-ligand 1 (PD-L1) blockade in mouse models. We demonstrate that combined ATR and PD-L1 inhibition causes improved antitumor response than PD-L1 alone as the second-line treatment in SCLC. This study shows that targeting ATR up-regulates major histocompatibility class I expression in preclinical models and SCLC clinical samples collected from a first-in-class clinical trial of ATR inhibitor, berzosertib, with topotecan in patients with relapsed SCLC. Targeting ATR represents a transformative vulnerability of SCLC and is a complementary strategy to induce STING-interferon signaling\u2013mediated immunogenicity in SCLC.<\/jats:p>","DOI":"10.1126\/sciadv.ado4618","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T13:59:07Z","timestamp":1727445547000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":85,"title":["ATR inhibition activates cancer cell cGAS\/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2414-8344","authenticated-orcid":true,"given":"Hirokazu","family":"Taniguchi","sequence":"first","affiliation":[{"name":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA."},{"name":"Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0626-9011","authenticated-orcid":true,"given":"Subhamoy","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8592-6528","authenticated-orcid":true,"given":"Nobuyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan."},{"name":"Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5697-6721","authenticated-orcid":true,"given":"Avisek","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Caeser","sequence":"additional","affiliation":[{"name":"Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3548-9227","authenticated-orcid":true,"given":"Yingqian A.","family":"Zhan","sequence":"additional","affiliation":[{"name":"Marie-Jos\u00e9e and Henry R. 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