학술논문
Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198.
Document Type
Article
Author
Molenaar, Remco J.; Botman, Dennis; Smits, Myrthe A.; Hira, Vashendriya V.; van Lith, Sanne A.; Stap, Jan; Henneman, Peter; Khurshed, Mohammed; Lenting, Krissie; Mul, Adri N.; Dimitrakopoulou, Dionysia; van Drunen, Cornelis M.; Hoebe, Ron A.; Radivoyevitch, Tomas; Wilmink, Johanna W.; Maciejewski, Jaroslaw P.; Vandertop, W. Peter; Leenders, William P.; Bleeker, Fonnet E.; van Noorden, Cornelis J.
Source
Subject
*ISOCITRATE dehydrogenase
*RADIATION-protective agents
*CANCER cells
*GENETIC mutation
*OXIDATIVE stress
*HETEROZYGOSITY
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Language
ISSN
0008-5472
Abstract
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 IDH1R132Hmutation 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. [ABSTRACT FROM AUTHOR]