Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer

Ovarian cancer remains the leading cause of gynecologic cancer mortality, yet nearly half of BRCA1/2-mutated ovarian cancer patients eventually develop resistance to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we investigated whether lixumistat, a novel oxidative phosphorylation (OXPHOS) inhibitor, could overcome PARP inhibitor resistance in preclinical BRCA1/2-mutated ovarian cancer models. Long-term olaparib exposure generated olaparib-resistant BRCA-mutated ovarian cancer cell lines and patient-derived tumor xenograft (PDTX) models. Olaparib-resistant cells exhibited elevated OXPHOS activity. Lixumistat, when combined with olaparib, demonstrated synergistic antitumor effects in both olaparib-sensitive and -resistant cell lines and PDTX models. Switching from olaparib monotherapy to combination markedly suppressed tumor growth in partially resistant and acquired-resistant PDTX models. These results suggest that early integration of lixumistat could enhance efficacy and delay PARP inhibitor resistance. Mechanistically, lixumistat restores PARP inhibitor sensitivity by inhibiting the OXPHOS–NAD⁺-poly(ADP)-ribosylation (PARylation) axis, which reduces NAD⁺ availability and subsequent PARylation. Exogenous NAD⁺ reversed these effects. Additionally, lixumistat downregulated the SNAIL-mediated IL6-phosphorylated STAT3 and phosphorylated retinoblastoma pathway, impairing cell-cycle progression and further enhancing PARP inhibitor efficacy. Together, these findings identify a novel OXPHOS-associated mechanism underlying PARP inhibitor resistance and establish lixumistat as a promising combinatorial strategy to potentiate PARP inhibitors in both PARP inhibitor-naive and -resistant ovarian cancer.