Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198.

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

Index: Cancer Res. 75 , 4790-802, (2015)

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Abstract

Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1(R132H), 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 IDH1(R132H) that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1(R132H) 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 IDH1(R132H) 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 IDH1(R132H) inhibitors in these patients may limit irradiation efficacy in this setting.©2015 American Association for Cancer Research.