{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:28:07Z","timestamp":1789014487001,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of NCI, CCR","award":["ZIA BC011525"],"award-info":[{"award-number":["ZIA BC011525"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>High-grade serous ovarian cancer (HGSOC) is the most common (~80%) and lethal ovarian cancer subtype in the United States, characterized by TP53 mutations and DNA repair defects causing chromosomal instability (CIN). KIF18A is an essential cytoskeletal motor protein for cell division in CIN+ cancer cells, but it is not necessary for cell division in normal cells. Therefore, KIF18A represents a promising target for therapeutic interventions in CIN+ cancers. We investigated the use of a novel KIF18A inhibitor ATX020, for selectively targeting CIN+ HGSOC cells using growth inhibition assays, invasion assays, immunoassays, cell cycle analysis, and immunofluorescence techniques. Using DepMap and flow cytometry, we classified a panel of HGSOC cell lines based on aneuploidy scores (AS) and ploidy levels and identified a correlation between these classifications and sensitivity against ATX020. ATX020 induced cytotoxicity through mitotic arrest and DNA damage, and reduced tumor growth in HGSOC with high aneuploidy scores (AS). Mechanistically, ATX020 blocks KIF18A\u2019s plus-end movement on spindle fibers, increasing spindle length, resulting in chromosomal mis-segregation, aneuploidy, and DNA damage. Our findings suggest that ATX020 inhibits CIN+ HGSOC cells mainly by inducing mitotic arrest and DNA damage, disrupting KIF18A\u2019s function crucial for mitosis.<\/jats:p>","DOI":"10.3390\/cells14231863","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T11:43:22Z","timestamp":1764157402000},"page":"1863","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The KIF18A Inhibitor ATX020 Induces Mitotic Arrest and DNA Damage in Chromosomally Instable High-Grade Serous Ovarian Cancer Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Jayakumar","family":"Nair","sequence":"first","affiliation":[{"name":"Women\u2019s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3675-2760","authenticated-orcid":false,"given":"Tzu-Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"Women\u2019s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6808-5109","authenticated-orcid":false,"given":"Maureen","family":"Lynes","sequence":"additional","affiliation":[{"name":"Accent Therapeutics, Lexington, MA 02421, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjoy","family":"Khan","sequence":"additional","affiliation":[{"name":"Accent Therapeutics, Lexington, MA 02421, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8090-2941","authenticated-orcid":false,"given":"Serena","family":"Silver","sequence":"additional","affiliation":[{"name":"Accent Therapeutics, Lexington, MA 02421, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Women\u2019s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","first-page":"151","article-title":"Pathogenesis of ovarian cancer: Lessons from morphology and molecular biology and their clinical implications","volume":"27","author":"Kurman","year":"2008","journal-title":"Int. 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