Abstract 3607: Inhibition of mutant IDH enzymes reduces production of 2-HG but does not restore wild type IDH activity in vitro or in vivo

Abstract

Abstract Mutations in isocitrate dehydrogenase (IDH) 1 and 2 occur in variety of malignancies, and notably >70% of low grade gliomas. These mutations lead to neomorphic enzymatic activity that results in the production of the oncometabolite (D)-2-hydroxyglutarate (2-HG) through the consumption of NADPH. IDH mutant cells and tumors have been shown to have heightened sensitivity to reactive oxygen species (ROS) and radiation, though it is unclear if this sensitivity is due to a loss of IDH wild type enzymatic NADPH production, the neoenzymatic activity of the mutant enzyme, or a combination of these activities. In support of the hypothesis that sensitivity to ROS and radiation is due to a reduced IDH wild type activity in IDH mutant cells, we previously demonstrated that combined treatment of mutant IDH mouse xenografts with AG-881, a potent orally available mutant IDH inhibitor, and radiation resulted in superior tumor growth inhibition than either modality alone. To extend this investigation, we have now developed a novel assay to read out the wild type activity of IDH1/2 enzymes in both cell-based assays and mouse xenograft models. Using an isotopic labeling approach that allows us to fully differentiate the activity of wild type IDH1/2 from the mutant enzymatic activity in the same cell or tumor, we observed that mutant IDH cells and tumors have a significantly reduced level of wild type IDH1/2 activity compared to normal tissue or IDH wild type tumors. Importantly, pharmacologic inhibition of mutant IDH1/2 that resulted in >90% reduction in 2-HG production in mutant cells and tumors did not restore the IDH1/2 wild type activity. These data support our previous observations and suggest that therapeutic strategies targeting the reduced activity of wild type IDH enzymes, such as modalities that induce ROS or treatment with radiation, would be effective when combined with mutant IDH inhibitors. Citation Format: Katie Sellers, Taryn Sleger, Sebastien Ronseaux, Rohini Narayanaswamy, Christine Hudson, Thomas Roddy, Brandon Nicolay. Inhibition of mutant IDH enzymes reduces production of 2-HG but does not restore wild type IDH activity in vitro or in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3607.