Endogenous replication stress creates a unique therapeutic window for ALC1 targeting.

Loss of ALC1 markedly sensitizes ovarian cancer cells to PARPi, including resistant and CCNE1-amplified tumors, with a wide therapeutic index.

• Why it matters: Overcoming PARPi resistance and expanding their effectiveness in homologous recombination-proficient tumors remains a critical challenge in ovarian cancer treatment.
• What they did: The study used cell lines, xenografts, and patient-derived models to show that ALC1 depletion enhances PARPi sensitivity across different genetic contexts, with endogenous phospho-T21 RPA2 as a predictive biomarker.
• The result: Targeting ALC1 circumvents resistance, spares nonmalignant cells, and offers a promising, biomarker-guided approach to improve PARPi therapy safety and efficacy.