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Specifically, MYC\u2010driven non\u2010neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high\u2010throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First\u2010in\u2010class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models. Mechanistically, ATR inhibition abrogated S\u2010phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High\n                    <jats:italic>CDKN1A<\/jats:italic>\n                    \/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of\n                    <jats:italic>ERCC5<\/jats:italic>\n                    \/XPG were predictive of increased combination efficacy. Importantly, MYC\u2010driven non\u2010neuroendocrine tumors which are resistant to first\u2010line therapies show reduced\n                    <jats:italic>CDKN1A<\/jats:italic>\n                    \/p21 expression and increased\n                    <jats:italic>ERCC5<\/jats:italic>\n                    \/XPG indicating they are primed for response to lurbinectedin\u2013berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202217313","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T02:32:31Z","timestamp":1690338751000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["ATR inhibition augments the efficacy of lurbinectedin in small\u2010cell lung cancer"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-2847","authenticated-orcid":false,"given":"Christopher 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