19. Jing Luo, PhD

PARP inhibitors (PARPis) have shown significant efficacy in prostate cancer (PCa) with BRCA1/2 mutations or homologous recombination (HR) deficiencies. However, the predictive value of non-BRCA gene alterations for PARPi responses has not consistently proven reliable. To answer these questions, we conducted genome-wide CRISPR-Cas9 knockout screens in prostate cancer cells, unveiling the previously unrecognized role of the NDUFAF4 gene in modulating the response to PARP inhibitors. PCa cells lacking NDUFAF4 exhibited higher sensitivity to PARPi due to disrupted mitochondrial function. Mechanistically, we found that NDUFAF4 knockout or the Complex 1 inhibitor IACS-010759 combined with PARPi induces synergistic effects by triggering ROS-dependent oxidative DNA damage. Moreover, the combination of IACS-010759 and Olaparib resulted in significantly greater tumor regression compared to either agent alone in prostate patient-derived xenograft (PDX) models. These findings broaden the potential application of PARPi beyond HR-deficient tumors and propose that combining a Complex 1 inhibitor with PARPi could represent a promising therapeutic strategy.