Abstract 2918: Wild-type IDH1 inhibition induces BRCAness to sensitize pancreatic cancer to PARP inhibitors

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal cancers in the United States. Homologous recombination (HR) deficiency has facilitated the development of targeted therapies like Poly (ADP-ribose) polymerase (PARP) inhibitors. However, only 10-20% of PDAC cases exhibit HR deficiency, leaving a majority of patients without targeted therapeutic options. This study identifies wild-type isocitrate dehydrogenase 1 (wtIDH1), a cytosolic metabolic enzyme, as a critical factor for HR repair in HR-proficient tumors. Inhibiting wtIDH1 disrupts genomic stability, sensitizing HR-proficient PDAC to PARP inhibitors. Methods: We evaluated wtIDH1 inhibition on HR and non-homologous end joining (NHEJ) activity using DNA repair protein quantification and reporter assays. We also examined its effect on histone methylation. Synergistic anti-tumor effects of IDH1 and PARP inhibitors were assessed through drug combination assays, DNA damage response analysis, and apoptosis quantification. In vivo efficacy was studied in xenograft and orthotopic murine PDAC models. Results: WtIDH1 inhibition impaired HR repair pathways, induced a BRCAness phenotype by reducing α-ketoglutarate levels, and promoted histone hypermethylation. Combination therapy with IDH1 and PARP inhibitors significantly reduced cell viability in vitro and amplified DNA damage and apoptosis markers. In murine models, co-administration of ivosidenib and olaparib synergistically reduced tumor growth and improved survival compared to monotherapies. Conclusion: This study uncovers a novel strategy to target HR-proficient PDAC using combined IDH1 and PARP inhibition, demonstrating significant preclinical efficacy. Future studies will focus on optimizing and translating this approach into clinical practice. Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Soubhi Tahhan, Alexander W. Loftus, Faith Nakazzi, Semmer A. Ali, Vinayak Uppin, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Wild-type IDH1 inhibition induces BRCAness to sensitize pancreatic cancer to PARP inhibitors [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 2918.