{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:25:39Z","timestamp":1790760339601,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck","doi-asserted-by":"publisher","award":["10.13039\/100009945"],"award-info":[{"award-number":["10.13039\/100009945"]}],"id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009945","name":"Merck","doi-asserted-by":"publisher","award":["MR\/N017838"],"award-info":[{"award-number":["MR\/N017838"]}],"id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011856","name":"MRC iCASE studentship grant","doi-asserted-by":"publisher","award":["10.13039\/100009945"],"award-info":[{"award-number":["10.13039\/100009945"]}],"id":[{"id":"10.13039\/501100011856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011856","name":"MRC iCASE studentship grant","doi-asserted-by":"publisher","award":["MR\/N017838"],"award-info":[{"award-number":["MR\/N017838"]}],"id":[{"id":"10.13039\/501100011856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Ataxia telangiectasia and Rad-3 related kinase (ATR) signals DNA lesions and replication stress (RS) to the S and G2\/M checkpoints and DNA repair pathways making it a promising target to exploit the dysregulated DNA damage response in cancer. ATR inhibitors (ATRi) are under clinical investigation as monotherapy and in combination with other anticancer agents. Molecular determinants of sensitivity to ATRi are common in ovarian cancer, suggesting the therapeutic potential of ATRi. We investigated the cytotoxicity of the ATRi, VE-821, in a panel of human ovarian cancer cell lines. High grade serous (HGS) cell lines were significantly more sensitive to VE-821 than non-HGS (p \u2264 0.0001) but previously identified determinants of sensitivity (TP53, ATM and BRCA1) were not predictive. Only low RAD51 (p = 0.041), TopBP1 (p = 0.026) and APOBEC3B (p = 0.015) protein expression were associated with increased VE-821 sensitivity. HGS cells had increased levels of RS (pRPASer4\/8 and \u03b3H2AX nuclear immunofluorescence), and elevated RS predicted sensitivity to VE-821 independently of the cell line subtype. These data suggest that functional assessment of RS biomarkers may be a better predictive biomarker of ATRi response than any single aberrant gene in ovarian cancer and potentially other cancers.<\/jats:p>","DOI":"10.3390\/cells11152361","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T21:01:24Z","timestamp":1659387684000},"page":"2361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response"],"prefix":"10.3390","volume":"11","author":[{"given":"Alice","family":"Bradbury","sequence":"first","affiliation":[{"name":"Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank T.","family":"Zenke","sequence":"additional","affiliation":[{"name":"Translational Innovation Platform Oncology, Merck KGaA, Frankfurt Strasse 250, D-64293 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1369-1843","authenticated-orcid":false,"given":"Nicola J.","family":"Curtin","sequence":"additional","affiliation":[{"name":"Newcastle University Center for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6676-9224","authenticated-orcid":false,"given":"Yvette","family":"Drew","sequence":"additional","affiliation":[{"name":"BC Cancer Vancouver, Departments of Medicine and Obstetrics and Gynecology, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 4E6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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