PARP inhibition induces a redox-dependent dormant reservoir vulnerable to disulfiram in high-grade serous ovarian cancer

Information from the abstract

Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC) is increasingly driven by non-genetic drug-tolerant dormant cell populations, yet the adaptive programs sustaining these cells remain poorly understood. Here, we established a longitudinal model of PARPi-induced dormancy and proliferative recovery using authenticated HGSOC cell lines spanning low, intermediate, and high homologous recombination deficiency (HRD) contexts. PARPi treatment generated a reversible reservoir enriched in polyploid giant cancer cells (PGCCs), with distinct recovery trajectories across HRD contexts. Despite heterogeneous metabolic, mesenchymal, and stress-adaptive remodeling, integrated transcriptomic and proteomic analyses identified a conserved dependence on redox homeostasis during dormancy. Transcriptomics-guided functional screening identified disulfiram as a candidate therapeutic strategy targeting this shared vulnerability. Disulfiram synergized with PARPi to disrupt ALDH-associated redox buffering, increase reactive oxygen species, enhance DNA damage, and deplete the PGCC-enriched dormant reservoir. Antioxidant rescue experiments supported oxidative stress as a key mediator of this effect. Live-cell time-lapse imaging further demonstrated that a subset of PGCCs generated mononuclear progeny following PARPi withdrawal, supporting their contribution to post-treatment repopulation. Importantly, the disulfiram-PARPi combination durably suppressed clonogenic recovery after drug withdrawal while exhibiting preferential cytotoxicity toward HGSOC cells relative to the non-malignant epithelial models tested. Together, these findings demonstrate that, despite heterogeneous adaptive responses across HRD contexts, PARPi-induced dormant HGSOC cells converge on a shared redox-dependent vulnerability. Targeting ALDH-associated redox homeostasis with disulfiram represents a mechanistically supported strategy to eliminate recovery-competent dormant cells and potentially delay PARPi resistance and disease recurrence.

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Related topics: PARP inhibition in cancer therapy · Endoplasmic Reticulum Stress and Disease · Redox biology and oxidative stress