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Ltd."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    High-grade serous ovarian cancer (HGSOC) is a poor prognostic disease, especially in\n                    <jats:italic>BRCA1<\/jats:italic>\n                    \/\n                    <jats:italic>2<\/jats:italic>\n                    wild-type (BRCA-WT) patients with homologous recombination (HR) proficiency. These patients often show limited response to both platinum-based chemotherapy and PARP inhibitors. HR and non-homologous end joining (NHEJ) are the two major DNA double-strand break (DSB) repair pathways. HR is a precise repair mechanism for DSBs but is limited to S and G2 phases. In contrast, NHEJ functions more broadly throughout the cell cycle, including G1. We investigated whether inhibiting the G2\/M checkpoint kinases PLK1 or WEE1 individually could disrupt mitotic control and expose therapeutic vulnerabilities in BRCA-WT\/HR-proficient HGSOC cells. We evaluated cell cycle\u2013targeted strategies to overcome HR-proficient chemoresistance using either volasertib (a selective PLK1 inhibitor) or adavosertib (a potent WEE1 inhibitor) in BRCA-WT\/HR-proficient and BRCA-mutant\/HR-deficient HGSOC models. Both agents induced DNA damage, impaired HR repair (reduced RAD51 foci), and triggered mitotic catastrophe\u2014a form of cell death caused by defective mitosis and unresolved DNA damage\u2014in BRCA-WT cells. Volasertib caused polyploidy and abnormal spindle formation, indicating mitotic slippage and cytokinesis failure, whereas adavosertib abrogated the G2\/M checkpoint, forcing premature mitotic entry. In contrast, BRCA-mutant cells were resistant to either volasertib or adavosertib, consistent with sustained and functional NHEJ activity. This resistance was restored by the pharmacological or genetic inhibition of DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), a prominent component of NHEJ. Functional and xenograft models confirmed selective vulnerability of BRCA-WT tumors to either PLK1 or WEE1 inhibition. Our work highlights a mechanistic framework linking cell cycle checkpoint inhibition to DNA repair pathway selectivity, providing a rationale for targeting mitotic regulators in HR-proficient ovarian cancer\u2014a subgroup with high clinical unmet need.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08324-2","type":"journal-article","created":{"date-parts":[[2025,12,7]],"date-time":"2025-12-07T08:34:30Z","timestamp":1765096470000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["PLK1 or WEE1 inhibition targets homologous recombination repair proficiency in BRCA1\/2 wild-type high-grade serous ovarian cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Qian","family":"Xi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9989-8258","authenticated-orcid":false,"given":"Akiko","family":"Kunita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirei","family":"Ka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeko","family":"Nagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4143-4465","authenticated-orcid":false,"given":"Anh Quynh","family":"Duong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Taguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kousuke","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenbun","family":"Sone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Shinozaki-Ushiku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Ushiku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-9780","authenticated-orcid":false,"given":"Yasushi","family":"Hirota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Kage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Katayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2468-9573","authenticated-orcid":false,"given":"Katsutoshi","family":"Oda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,7]]},"reference":[{"key":"8324_CR1","first-page":"209","volume":"71","author":"J Sung, Ferlay","year":"2021","unstructured":"Sung, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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