ArticleEMBO reports2026
Endogenous replication stress creates a unique therapeutic window for ALC1 targeting.
Article in EMBO reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
15 authors.
Funding
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers. 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.
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42897309What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.