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However, their durable benefit is severely limited by resistance and hematologic toxicity. PARPi are also largely ineffective in homologous recombination-proficient tumors, especially CCNE1-amplified cancers, which remain therapeutically intractable. We show that loss of the chromatin remodeler Amplified in Liver Cancer 1 (ALC1) markedly sensitizes serous ovarian cancer cells, xenografts, and patient-derived models to PARPi across both HRD and CCNE1-amplified contexts. Unlike other PARPi sensitizers, ALC1 depletion circumvents clinically relevant PARPi resistance while sparing BRCA wild-type and heterozygous nonmalignant cells, revealing an unusually wide therapeutic index. Mechanistically, this selectivity is dictated by intrinsic replication-stress burden, which renders cancer cells uniquely dependent on ALC1-mediated stress tolerance. Accordingly, collective data from cell line and patient samples reveal endogenous phospho-T21 RPA2 as a predictive biomarker of PARPi responsiveness following ALC1 targeting. These findings establish ALC1 targeting as a mechanistically grounded, biomarker-guided strategy to safely expand PARPi efficacy and support the clinical advancement of ALC1 inhibitors currently in Phase I trials.<\/jats:p>","DOI":"10.1038\/s44319-026-00966-3","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T12:42:52Z","timestamp":1792413772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endogenous replication stress creates a unique therapeutic window for ALC1 targeting"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4772-3332","authenticated-orcid":false,"given":"Lindsey N","family":"Aubuchon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna H","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2717-4858","authenticated-orcid":false,"given":"Samantha F","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6720-5293","authenticated-orcid":false,"given":"Kathleen E","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Lomonosova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Compadre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Kemper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vrutti","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellen","family":"Zoberi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5184-2089","authenticated-orcid":false,"given":"Tibebe A","family":"Teklemariam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dineo","family":"Khabele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9959-7024","authenticated-orcid":false,"given":"Elizabeth L","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M","family":"Mullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-0767","authenticated-orcid":false,"given":"Priyanka","family":"Verma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"966_CR1","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1038\/bjc.2012.451","volume":"107","author":"V Abkevich","year":"2012","unstructured":"Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, Smith-McCune K, Broaddus R, Lu KH, Chen J et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. 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