Abstract 512: Wild-type IDH1 inhibition induces homologous recombination deficiency and enhances PARP inhibitor sensitivity in pancreatic cancer.

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with limited therapeutic options. While PARP inhibitors benefit tumors with homologous recombination deficiency (HRD), fewer than 10-20% of PDAC cases harbor such mutations. The majority are homologous recombination proficient (HRP), representing a significant unmet need. Here, we identify wild-type isocitrate dehydrogenase 1 (wtIDH1) as a critical regulator of HR repair in HRP PDAC and propose a novel combinatorial strategy using IDH1 and PARP inhibition to induce synthetic lethality. Methods: We assessed the role of wtIDH1 in DNA repair using HR and non-homologous end joining (NHEJ) reporter assays, Western blotting, and chromatin modification analyses. Effects of IDH1 inhibition (ivosidenib) and PARP inhibition (olaparib), alone and combined, were evaluated in vitro through cell viability, apoptosis, and DNA damage assays. In vivo efficacy was tested in xenograft and orthotopic PDAC mouse models, including survival studies. Additionally, tumor biopsies from patients in the ongoing phase Ib clinical trial (NCT05209074) receiving ivosidenib were analyzed for HR pathway activity and chromatin alterations. Results: Pharmacologic wtIDH1 inhibition depleted α-ketoglutarate and induced histone hypermethylation, impairing HR repair and mimicking a BRCA-like phenotype in HRP PDAC cell lines (MiaPaCa-2, Panc-1). The combination of IDH1 and PARP inhibitors synergistically increased γ-H2AX accumulation and apoptosis, reducing cell viability. In vivo, dual therapy significantly suppressed tumor growth and extended survival compared to monotherapies. Importantly, tumor samples from NCT05209074 patients treated with ivosidenib exhibited decreased expression of HR repair proteins and epigenetic changes consistent with a BRCAness phenotype, supporting translational relevance. Conclusion: Our findings reveal a novel role for wtIDH1 in maintaining homologous recombination in PDAC. Inhibition of wtIDH1 functionally induces HR deficiency in HRP tumors, sensitizing them to PARP inhibition. This combination represents a promising therapeutic approach for the majority of PDAC patients lacking canonical HR mutations and warrants further translational development. Citation Format: Mehrdad Zarei, Priyashree Sunita, Alexander Loftus, Faith Nakazzi, Semmer Ali, Om Prajapati, Soubhi Tahhan, Hallie J Graor, Shakti Prasad Pattanayak, Sami Abul-Khoudoud, Luke D. Rothermel, Rui Wang, Jonathan R. Brody, Jordan M. Winter. Wild-type IDH1 inhibition induces homologous recombination deficiency and enhances PARP inhibitor sensitivity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 512.