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.
Highlights
Isocitrate dehydrogenase 1 (IDH1) and lDH2 are homodimeric enzymes that reversibly convert isocitrate to a-ketoglutarate with concomitant reduction of NADPþ to NADPH in the cytoplasm and mitochondria, respectively [1]
The reduced IDH-mediated NADPH production capacity of IDH1MT cells was confirmed in U251 and LN229 glioblastoma cell lines that stably overexpressed IDH1WT or IDH1R132H (Fig. 1B–D)
We hypothesized that the increased radiosensitivity of lDH1WT/R132H HCT116 cells was caused by increased vulnerability to oxidative stress, which is a result of reduced IDH-mediated NADPH production capacity
Summary
IDH1 and lDH2 are homodimeric enzymes that reversibly convert isocitrate to a-ketoglutarate (aKG) with concomitant reduction of NADPþ to NADPH in the cytoplasm and mitochondria, respectively [1]. Somatic heterozygous hotspot mutations in IDH1/2 (IDHMT) are observed in substantial percentages of various tumor types, such as glioma (80%), acute myeloid. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). IDHMT cause metabolic changes in cancer [2]. All IDHMT, of which IDH1R132H is the most prevalent in glioma, cause loss of enzymatic wild-type IDH (IDHWT) function [3,4,5]. IDHMT have a neo-enzymatic (gain of function) activity: it converts aKG and NADPH to D-2-hydroxyglutarate (D-2HG) and NADPþ. Because of the chemical similarities between D-2HG and aKG, D-2HG competitively inhibits aKG-
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