Impairment of oxidative metabolism compromises Rad51 recruitment and potentiates PARP inhibitor effectiveness in ovarian cancer

Abstract Background The treatment of ovarian cancer has significantly improved since the introduction of PARP inhibitors (PARPi), small molecules designed to directly target and kill cancer cells with deficiencies in homologous recombination (HR) pathway. However, nearly half of patients present with HR-proficient tumors, rendering them not eligible for PARPi-based therapies and underscoring the urgent need for alternative treatment strategies. Methods Oxidative metabolism has been altered either by silencing the mitochondria regulator PGC-1β or by using the OXPHOS inhibitor IACS-010759. The metabolic alterations were characterized by seahorse analysis and metabolomic profiling. DNA damage and repair were evaluated by immunofluorescence and confocal analysis. Efficacy and tolerability of the combination of PARP and OXPHOS inhibitors were investigated in preclinical trials employing patient-derived ovarian cancer xenografts. Results Our findings reveal that PGC-1β silencing sensitizes ovarian cancer cells to PARPi by impairing oxidative metabolism, reducing succinate levels and decreasing Fen1 succinylation and SUMOylation. The impairment of these post-translational modifications hinders Fen1 activation and prevents the recruitment of Rad51, resulting in a HR-deficient-like phenotype. The translational relevance of the findings has been validated using the OXPHOS inhibitor IACS-010759, which synergizes with PARPi to inhibit cancer cell proliferation, while sparing normal cells. Furthermore, the combination therapy delays tumor progression in ovarian cancer xenografts not responsive to PARPi, independently from their HR status. Conclusions Targeting mitochondrial metabolism depicts a novel mechanism to modulate DNA repair and enhance PARPi sensitivity. This approach broadens the therapeutic applicability of PARP inhibitors beyond HR-deficient tumors and offers promising avenues to overcome resistance in ovarian cancer treatment.