{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:21:43Z","timestamp":1791199303912,"version":"4.1.0"},"reference-count":69,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"701","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,6,21]]},"abstract":"<jats:p>\n                    Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (\n                    <jats:italic>BRCA<\/jats:italic>\n                    )\u2013mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein\/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant\n                    <jats:italic>BRCA<\/jats:italic>\n                    -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with\n                    <jats:italic>BRCA<\/jats:italic>\n                    -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (\n                    <jats:italic>BLM<\/jats:italic>\n                    ) and cyclin E1 (\n                    <jats:italic>CCNE1<\/jats:italic>\n                    ) overexpression or copy number gain\/amplification were seen in patients who derived durable benefit from CHK1i.\n                    <jats:italic>BRCA<\/jats:italic>\n                    reversion mutation in previously PARPi-treated\n                    <jats:italic>BRCA<\/jats:italic>\n                    -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork\u2013related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with\n                    <jats:italic>BRCA<\/jats:italic>\n                    -mutant HGSC.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.add7872","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T14:26:45Z","timestamp":1687357605000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":26,"title":["<i>BLM<\/i>\n                    overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor\u2013resistant\n                    <i>BRCA<\/i>\n                    -mutant ovarian cancer"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-2368","authenticated-orcid":true,"given":"Nitasha","family":"Gupta","sequence":"first","affiliation":[{"name":"Women\u2019s Malignancies Branch, 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(NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA."},{"name":"Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, OH 44195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-3252","authenticated-orcid":true,"given":"Ann","family":"McCoy","sequence":"additional","affiliation":[{"name":"Women\u2019s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Cimino-Mathews","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2331-0434","authenticated-orcid":true,"given":"Elizabeth 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