{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:03:22Z","timestamp":1785402202566,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,8]]},"group-title":"Cancer Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R37-CA286908"],"award-info":[{"award-number":["R37-CA286908"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Career Catalyst Grant from Susan G. Komen"},{"name":"Early-career investigator Award from Ovarian Cancer Research Fund Alliance"},{"name":"V-Scholar grant"},{"name":"Inaugural Pedal the Cause Grant by Alvin J. Siteman Cancer Center through The Foundation for Barnes-Jewish Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers (HGSOCs), but their long-term effectiveness is limited by the emergence of resistance and hematological toxicity. Moreover, PARPi are largely ineffective in HR-proficient HGSOCs, particularly tumors with\n                  <jats:italic>CCNE1<\/jats:italic>\n                  amplification, which exhibit marked therapeutic resistance and currently lack effective treatment options. Loss of a chromatin remodeling enzyme, Amplified in Liver Cancer 1 (ALC1), has been shown to enhance PARPi sensitivity. However, the clinical contexts in which ALC1 targeting will be clinically meaningful remain elusive. Here we demonstrate that ALC1 loss enhances PARPi sensitivity across HRD and\n                  <jats:italic>CCNE1<\/jats:italic>\n                  -amplified serous ovarian cancer lines, xenograft and patient-derived cells. ALC1 depletion can overcome clinically relevant mechanisms of PARPi resistance while having minimal effects in\n                  <jats:italic>BRCA<\/jats:italic>\n                  -wild-type or heterozygous non-cancerous cells. Consistent with this therapeutic safety, PARPi sensitivity upon ALC1 loss can be reliably predicted by the endogenous levels of phospho-T21 RPA2, a marker for replication stress which is typically higher in ovarian cancer cells compared to their normal counterparts. Together, our studies define the clinical contexts in which the therapeutic utility of PARPi can be expanded by targeting ALC1, whose inhibitors are currently in Phase I clinical trials.\n                <\/jats:p>","DOI":"10.64898\/2025.12.04.692458","type":"posted-content","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T01:20:24Z","timestamp":1765243224000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting ALC1 can safely expand the therapeutic utility of PARP inhibitors across high-grade serous ovarian cancers"],"prefix":"10.64898","author":[{"given":"Lindsey N.","family":"Aubuchon","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine; St. Louis, MO, 63110, USA"},{"name":"Cancer Biology Graduate Program, Washington University School of Medicine; St. Louis, MO, 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna H.","family":"Wong","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine; St. Louis, MO, 63110, USA"},{"name":"Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Siteman Cancer Center, Washington University; St. Louis, Missouri, USA"},{"name":"Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Siteman Cancer Center, Washington University School of Medicine; 4911 Barnes Jewish Hospital Plaza, St. Louis, Missouri 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha M.","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine; St. Louis, MO, 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha F.","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine; St. Louis, MO, 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Reddy","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine; 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