Abstract PR014: PARP Inhibition Beyond BRCA in Prostate Cancer: The Roles of MMS22L and NDUFAF4

Abstract PARP inhibitors (PARPis) have demonstrated significant efficacy in prostate cancer (PCa) patients harboring BRCA1/2 mutations. However, the predictive value of non-BRCA gene alterations for PARPi responsiveness remains inconsistent. To address this, we conducted genome-wide CRISPR-Cas9 knockout screens in PCa cell models, uncovering previously unrecognized roles for MMS22L and NDUFAF4 in modulating PARPi sensitivity (Tsujino et al, Nat Commun 2023; PMID: 36650183). Both genes are located in close proximity on chromosome 6q, a region frequently deleted in PCa (∼9%). MMS22L interacts with TONSL to form a complex essential for replication fork-associated homologous recombination repair (HRR). Emerging evidence suggests that the MMS22L-TONSL complex functions as an alternative or compensatory RAD51 loader when BRCA2-mediated HRR is impaired (Kuthethur et al, Science 2025; PMID: 41166468). Notably, the F722fs germline mutation in MMS22L, present in 1.5% of Ashkenazi Jewish PCa cases, correlates with increased risk and disease aggressiveness (Isaacs et al, Eur Urol Focus 2025; PMID: 40189997). Our results indicate that loss of MMS22L—both deep and shallow deletions—confers a BRCA-like sensitivity to PARP inhibition. Furthermore, our screens revealed a surprising enrichment of mitochondrial complex I-associated genes in castration-resistant prostate cancer (CRPC) cell lines. NDUFAF4, a mitochondrial complex I assembly factor, when knocked out or pharmacologically inhibited, synergistically enhances PARPi efficacy through induction of reactive oxygen species (ROS)-mediated oxidative stress. We demonstrate that NDUFAF4 deficiency increases oxidative stress, leading to oxidative DNA damage (promoting PARP dependency) and lipid peroxidation, which sensitizes cells to ferroptosis. Importantly, combining the mitochondrial complex I inhibitor metformin with the PARPi olaparib resulted in significantly greater tumor regression in CRPC xenograft models compared to monotherapy. These findings expand the potential applications of PARPis beyond BRCA-deficient tumors, providing novel insights into predictive biomarkers and combinatorial therapeutic strategies in PCa. Citation Format: Jing Luo, Kazuki Nishimura, Fu Gui, Muqing Li, Taraswi Mitra Ghosh, Haibo Yang, Li Jia. PARP Inhibition Beyond BRCA in Prostate Cancer: The Roles of MMS22L and NDUFAF4 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR014.