Abstract B139: Targeting wild-type IDH1 creates a PARP inhibitor vulnerability in pancreatic cancer
Parsa Rezvani, Mehrdad Zarei, Sami O. Abul-Khoudoud, Alexander W. Loftus, Priyashree Sunita, Faith Nakazzi, Semmer A. Ali, Sakineh Rezaei, Hallie J. Graor, Luke D. Rothermel, Jordan M. WinterAbstract
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies, with an estimated 5-year overall survival rate of around 13%. Current treatment options provide limited therapeutic benefit. The clinical efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in PDAC is largely restricted to the small subset of tumors with homologous recombination deficiency (HRD). Consequently, most patients with homologous recombination-proficient (HRP) disease lack effective targeted treatment options. Pharmacologic induction of a functional HRD (BRCAness) phenotype represents a promising strategy to expand the therapeutic utility of PARP inhibition. In this study, we investigated whether inhibition of wild-type isocitrate dehydrogenase 1 (wtIDH1) induces BRCAness and enhances sensitivity to PARP inhibition in HRP PDAC.
Methods:
Human pancreatic cancer cell lines (MiaPaCa-2 and PANC-1) were used to evaluate the effects of pharmacologic and genetic wtIDH1 inhibition on homologous recombination (HR) repair. Changes in BRCA1 and BRCA2 expression were assessed by qRT-PCR and Western blotting. DNA repair capacity was evaluated using HR and non-homologous end joining (NHEJ) reporter assays. The therapeutic effects of wtIDH1 inhibition alone and in combination with PARP inhibition were assessed using cell viability, apoptosis, and DNA damage assays. Antitumor activity was further evaluated in human PDAC xenograft models and an orthotopic KPC mouse model.
Results:
Pharmacologic and genetic inhibition of wtIDH1 reduced BRCA1 and BRCA2 expression and impaired HR repair, while having minimal effects on NHEJ. wtIDH1 inhibition induced a BRCAness phenotype and sensitized PDAC cells to PARP inhibition, resulting in reduced cell viability, increased DNA damage, and enhanced apoptosis. Combination therapy significantly suppressed tumor growth and prolonged survival in human PDAC xenograft and orthotopic KPC mouse models.
Conclusion:
wtIDH1 inhibition creates a therapeutically actionable BRCAness phenotype in HRP tumors by suppressing BRCA1/2 expression and impairing HR repair. This vulnerability sensitizes PDAC to PARP inhibition and supports combined wtIDH1 and PARP inhibition as a potential treatment strategy for patients with HRP PDAC.
Citation Format:
Parsa Rezvani, Mehrdad Zarei, Sami O. Abul-Khoudoud, Alexander W. Loftus, Priyashree Sunita, Faith Nakazzi, Semmer A. Ali, Sakineh Rezaei, Hallie J. Graor, Luke D. Rothermel, Jordan M. Winter. Targeting wild-type IDH1 creates a PARP inhibitor vulnerability in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B139.