American Association for Cancer Research
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Supplementary Figure S3 from Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

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posted on 2023-03-31, 00:14 authored by Remco J. Molenaar, Dennis Botman, Myrthe A. Smits, Vashendriya V. Hira, Sanne A. van Lith, Jan Stap, Peter Henneman, Mohammed Khurshed, Krissie Lenting, Adri N. Mul, Dionysia Dimitrakopoulou, Cornelis M. van Drunen, Ron A. Hoebe, Tomas Radivoyevitch, Johanna W. Wilmink, Jaroslaw P. Maciejewski, W. Peter Vandertop, William P. Leenders, Fonnet E. Bleeker, Cornelis J. van Noorden

The IDH1-mutant inhibitor AGI-5198 increases IDH-mediated NAPDH production capacity in IDH1-mutated cells.



Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1R132H, a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1R132H inhibitors in these patients may limit irradiation efficacy in this setting. Cancer Res; 75(22); 4790–802. ©2015 AACR.