Targeting ALC1 can safely expand the therapeutic utility of PARP inhibitors across high-grade serous ovarian cancers.

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. Approximately 50% of HGSOCs are homologous recombination-proficient (HRP), and within this group, about 20% harbor CCNE1 amplification (cyclin E1-high). PARPi are especially ineffective in HRP tumors and in CCNE1 -high HGSOCs, which represent a major unmet clinical need. 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 remains unclear. Here we demonstrate that ALC1 loss can enhance PARPi sensitivity across HRD and cyclin E1-high serous ovarian cancer lines, xenografts and patient-derived cells. ALC1 depletion can overcome several clinically relevant mechanisms of PARPi resistance, though its impact is limited in tumors with complete restoration of HR. Lower ALC1 expression correlates with longer progression-free survival and extended PARPi response. Importantly, ALC1 loss has minimal effects in BRCA -wild-type or BRCA -heterozygous non-cancerous fallopian tube cells, suggesting therapeutic safety. Increased PARPi sensitivity following ALC1 loss can be accurately predicted by endogenous single-stranded DNA levels, identifying a functional biomarker. Together, our studies define the clinical contexts in which the therapeutic utility of PARPi can be expanded by targeting ALC1, whose inhibitors are currently under evaluation in Phase I clinical trials.