Abstract 7125: Inhibition of IDH1 impairs homologous recombination and induces sensitivity to PARP inhibitor in pancreatic cancer
Authors: Zarei Mehrdad , Hajihassani Omid , Graor Hallie J. , Loftus Alexander W. , Tahhan Soubhi , Nakazzi Faith , Naji Parnian , Rothermel Luke D. , Brody Jonothan R. , Winter Jordan M. 
Published: March 2024

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related deaths in the United States. While Poly (ADP-ribose) polymerase (PARP) inhibitors hold promise in treating PDAC with Homologous Recombination Deficiency (HRD). However, HRD occurs in only 10% of cases, leaving 90% with intact Homologous Recombination Proficiency (HRP). Our research highlights the key role of wild-type isocitrate dehydrogenase 1 (IDH1) in maintaining cellular function. We found that inhibiting IDH1 increases DNA damage, suppressing the DNA repair pathway crucial for genomic integrity. This makes cancer cells susceptible to PARP inhibitors, offering a new PDAC treatment approach.

Methods: The effect of IDH1 inhibition (Ivosidenib) combined with PARP inhibition (Olaparib) on in vitro growth inhibition were assessed through Trypan blue and PicoGreen in drug combination assays. Additionally, we investigated the molecular mechanism underlying the synergistic effects of drug combination. To further evaluate the therapeutic potential of IDH1 inhibition in combination with PARP inhibitors, we examined tumor growth in xenograft models of PDAC in athymic nude mice.

Results: Our data report that, mechanistically, IDH1 inhibition decreased expression of HR DNA repair pathway molecules, such as BRCA1 and BRCA2, and leading to decreased HR repair efficiency in pancreatic cancer cells. Short-term cell viability data demonstrated that targeting IDH1 with ivosidenib when combined with DNA-damaging agent (Olaparib) had a synergistic effect in HRP cell lines (MiaPaCa-2 and Panc-1) with a positive synergy score and Bliss score greater than 1. Additionally, we assessed long-term cell survival using colony formation assays, which yielded a dramatic reduction in cell survival for both Panc1 and MiaPaCa-2 cells when olaparib was combined with ivosidenib, as compared to single-agent controls. Consequently, this reduction increased the levels of apoptosis induced by olaparib. Furthermore, we discovered that these two compounds complemented each other in DNA damage response, leading to an increase in the DNA damage biomarker γ-H2AX. In vivo studies using xenograft models demonstrated that the combination of ivosidenib and olaparib synergistically enhanced anti-tumor activity as compared to either single-agent used alone.

Conclusion: Our data provides insights into the mechanisms underlying the susceptibility of PDAC tumor growth to a dual treatment approach involving an IDH1 inhibitor and a PARP inhibitor, particularly in the context of HRP cancer. This highlights the promise of precision medicine for pancreatic cancer treatment, though further pre-clinical studies are needed for validation and refinement.

Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Alexander W. Loftus, Soubhi Tahhan, Faith Nakazzi, Parnian Naji, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Inhibition of IDH1 impairs homologous recombination and induces sensitivity to PARP inhibitor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7125.