Abstract 5386: Metabolic regulation of PARP inhibitor response in ovarian cancer cells

Abstract Ovarian cancer (OvCa) is the most lethal gynecologic cancer due to high mortality from therapeutic resistance. Recently, PARP inhibitors (PARPi) have shown efficacy in treating OvCa, and patients with DNA repair pathway defects are now on PARPi maintenance. However, heterogeneous responses and resistance to therapy limit the clinical efficacy of PARPi treatment. Catalytic activation of the PARP1 enzyme consumes NAD+, a metabolite coenzyme for redox reactions and a key regulator of energy metabolism. PARP inhibitors can change the metabolic state of cells by inhibiting PARP1 activation and altering cellular NAD+ levels, but the role of metabolic dysregulation in PARPi resistance remains unclear. Here, we show that PARPi-resistant ovarian cancer cells have elevated NAD+ biosynthesis through the NAD+ salvage pathway. Gene expression analysis using RNA sequencing and metabolomic analysis using metabolic profiling have identified key pathways downstream of NAD+ biosynthesis that contribute to PARPi resistance. We also demonstrated that the metabolic changes caused by high NAD+ biosynthesis in PARPi-resistant cells cause cell cycle arrest at the G0/G1 phase and increase cellular quiescence and cell motility. Inhibition of the NAD+ salvage pathway and reduction of NAD+ levels within PARPi-resistant cells reverse cellular quiescence and cell migration, ultimately increasing the PARPi response in these cells. In summary, our results demonstrate that elevated NAD+ biosynthesis in ovarian cancer cells causes PARP inhibitor resistance by altering the metabolic state of these cells. Furthermore, inhibition of the NAD+ salvage pathway enhances the efficacy of PARP inhibitor-mediated control of ovarian cancer growth. Supported by grants from the NCI SPORE and CRF to S.C. Citation Format: Subin Myong, Hardik Shah, Benedikt Nagele, Anh Q. Nguyen, Sridevi Challa. Metabolic regulation of PARP inhibitor response in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5386.