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

Ovarian cancer remains the leading cause of gynecologic cancer-related mortality worldwide. Although poly(ADP-ribose) polymerase (PARP) inhibitors show remarkable efficacy in BRCA1/2-mutated ovarian cancer, nearly half of patients eventually develop resistance. 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. Lixumistat, alone or combined with olaparib, was evaluated in vitro and in vivo. Olaparib-resistant cells exhibited elevated OXPHOS activity, and combining lixumistat with olaparib produced synergistic antitumor effects in both olaparib-sensitive and -resistant cell lines and PDTX models. Switching from olaparib monotherapy to combination therapy 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 inhibited the OXPHOS-NAD⁺-poly(ADP)-ribosylation (PARylation) axis, thereby reducing NAD⁺ availability and PARylation to restore PARP inhibitor sensitivity. Notably, exogenous NAD⁺ supplementation reversed these effects. Additionally, lixumistat downregulated the SNAIL-phosphorylated RB 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-naïve and -resistant ovarian cancer.