Abstract LB-B05: Targeting IDH1 inhibits survival and growth of pancreatic cancer cells

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) cells have elevated levels of reactive oxygen species (ROS) compared to adjacent normal cells. Although ROS play a role in pancreatic carcinogenesis, the accumulation of excess ROS at later stages of cancer development threaten PDA cell viability. Therefore, adaptive mechanisms to neutralize excess ROS are critical for PDA cell survival. Recently, we discovered the regulatory RNA binding protein, HuR (ELAVL1), protects PDA cells under oxidative stressors, like chemotherapy and nutrient deprivation, by upregulating the NADPH-generating enzyme, isocitrate dehydrogenase 1 (IDH1) through post-transcriptional stabilization of the RNA transcript. This action enhances PDA reductive power under oxidative stress. We hypothesized that IDH1 would be an effective target to treat PDA under its native harsh microenvironment. We deleted IDH1 from isogenic PDA cells using CRISPR gene editing technology and studied the phenotypic impact under physiologic stress. Under both normal culture conditions and nutrient deprivation, IDH1-/- cells had increased ROS as measured by a DCFDA assay, and decreased cell viability as measured by the PicoGreen DNA quantitation assay. Furthermore, IDH1-/- cells were more susceptible to chemotherapy treatment in vitro (gemcitabine or 5-FU) compared with control cells. In vivo experiments revealed that IDH1-/- cells have reduced ability to engraft and grow as xenografts. Taken together, these results suggest that targeting wild type IDH1 is a compelling therapeutic strategy to treat PDA cells, particularly in the context of their extreme and austere microenvironment. Citation Format: Ali Vaziri-Gohar, Katerina Dukleska, Jonathan R. Brody, Jordan M. Winter. Targeting IDH1 inhibits survival and growth of pancreatic cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B05.