Abstract B039: Wild-Type IDH1 inhibition enhances PARP inhibitor sensitivity in pancreatic cancer

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States. While poly(ADP-ribose) polymerase (PARP) inhibitors offer therapeutic benefit in tumors with homologous recombination (HR) deficiency, such mutations are present in only 10–20% of PDAC cases. This study reveals that the cytosolic enzyme wild-type isocitrate dehydrogenase 1 (wtIDH1) plays a key role in supporting HR repair. Pharmacologic inhibition of wtIDH1 in HR-proficient PDAC disrupts genomic maintenance mechanisms and DNA repair pathways, thereby sensitizing tumors to PARP inhibition. Methods: We assessed the effect of wtIDH1 blockade on DNA repair capacity using HR and non-homologous end joining (NHEJ) reporter systems and quantified changes in DNA repair proteins. Histone methylation patterns were analyzed to evaluate chromatin alterations. Synergy between IDH1 and PARP inhibition was determined via viability assays, DNA damage response profiling, and apoptosis analysis. In vivo efficacy was evaluated using xenograft and orthotopic PDAC mouse models treated with IDH1 and PARP inhibitors. Results: Pharmacologic inhibition of wtIDH1 impaired HR repair, mimicked a BRCA-mutated phenotype by depleting α-ketoglutarate, and triggered histone hypermethylation. Combined inhibition of wtIDH1 inhibitor and PARP significantly reduced cell viability, increased DNA damage, and elevated apoptosis in vitro. In preclinical PDAC models, the combination therapy substantially suppressed tumor growth and improved survival compared to either treatment alone. Conclusion: Our findings demonstrate that targeting wtIDH1 induces a state of functional HR deficiency in PDAC, thereby sensitizing tumors to PARP inhibitors. This strategy offers a promising therapeutic avenue for the majority of PDAC patients lacking innate HR defects and warrants further translational development. Citation Format: Mehrdad Zarei, Priyashree Sunita, Alexander W. Loftus, Faith Nakazzi, Soubhi Tahhan, Semmer A. Ali, Hallie J. Graor, Luke D. Rothermel, Rui Wang, Jonathan R. Brody, Jordan M. Winter. Wild-Type IDH1 inhibition enhances PARP inhibitor sensitivity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B039.