{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:44:54Z","timestamp":1790790294723,"version":"4.1.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":38,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA215453-02"],"award-info":[{"award-number":["R01 CA215453-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"America Association of Cancer Research","award":["18-40-12-SULE"],"award-info":[{"award-number":["18-40-12-SULE"]}]},{"DOI":"10.13039\/100001512","name":"National Brain Tumor Society","doi-asserted-by":"publisher","award":["2021"],"award-info":[{"award-number":["2021"]}],"id":[{"id":"10.13039\/100001512","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1\/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, \u03b1-ketoglutarate (\u03b1KG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as \u2018BRCAness\u2019, which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1\/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1\/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1\/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1\/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1\/2-mutant cancers and support the development of this combination in future clinical trials.<\/jats:p>","DOI":"10.1093\/narcan\/zcab018","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T15:31:15Z","timestamp":1621265475000},"source":"Crossref","is-referenced-by-count":34,"title":["Targeting IDH1\/2 mutant cancers with combinations of ATR and PARP inhibitors"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6782-1899","authenticated-orcid":false,"given":"Amrita","family":"Sule","sequence":"first","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine , New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinny","family":"Van\u00a0Doorn","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine , New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjini K","family":"Sundaram","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine , New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachita","family":"Ganesa","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine , New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan\u00a0C","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale School of Medicine , New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3255-0467","authenticated-orcid":false,"given":"Ranjit\u00a0S","family":"Bindra","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale University School of Medicine , New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"2022082912274469900_B1","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1056\/NEJMoa0808710","article-title":"IDH1 and IDH2 mutations in gliomas","volume":"360","author":"Yan","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2022082912274469900_B2","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJMoa0903840","article-title":"Recurring mutations found by sequencing an acute myeloid leukemia genome","volume":"361","author":"Mardis","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2022082912274469900_B3","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/ng.2813","article-title":"Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas","volume":"45","author":"Jiao","year":"2013","journal-title":"Nat. Genet."},{"key":"2022082912274469900_B4","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1038\/ng.2359","article-title":"Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma","volume":"44","author":"Krauthammer","year":"2012","journal-title":"Nat. Genet."},{"key":"2022082912274469900_B5","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1002\/path.2913","article-title":"IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours","volume":"224","author":"Amary","year":"2011","journal-title":"J. Pathol."},{"key":"2022082912274469900_B6","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1158\/1078-0432.CCR-13-1333","article-title":"Molecular pathways: isocitrate dehydrogenase mutations in cancer","volume":"22","author":"Clark","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"2022082912274469900_B7","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/nature09132","article-title":"Cancer-associated IDH1 mutations produce 2-hydroxyglutarate","volume":"465","author":"Dang","year":"2010","journal-title":"Nature"},{"key":"2022082912274469900_B8","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41588-017-0001-z","article-title":"Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence","volume":"50","author":"Turcan","year":"2018","journal-title":"Nat. Genet."},{"key":"2022082912274469900_B9","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1158\/1078-0432.CCR-20-1827","article-title":"Targeting isocitrate dehydrogenase mutations in cancer: emerging evidence and diverging strategies","volume":"27","author":"Waitkus","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"2022082912274469900_B10","first-page":"15","article-title":"2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity","volume":"9","author":"Parker","year":"2017","journal-title":"Science Transl. Med"},{"key":"2022082912274469900_B11","doi-asserted-by":"crossref","first-page":"eaaz3221","DOI":"10.1126\/sciadv.aaz3221","article-title":"Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas","volume":"6","author":"Wang","year":"2020","journal-title":"Sci. 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