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

Abstract

Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1 R132H , a structural alteration that leads to catalysis of a-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.

Roles of IDH1/2 and TET2 mutations in myeloid disorders

“…An effect of IDH1 mutation on DNA damage/repair was also demonstrated by Molenaar et al using an HCT116 cell line expressing mutant IDH1-R132 [53]. In this system, decreased NADPH production due to the mutated IDH1 enzyme increased ROS, leading to DNA damage induced by oxidative stress (Fig.…”

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients withIDH1-mutated orIDH2-mutated solid tumours

“…Patients with IDH1/2 -mutated glioblastoma have a prolonged survival and better radiotherapy/chemotherapy response when compared with IDH1/2 wild-type counterparts,14 32 33 while in chondrosarcoma a correlation between mutation and survival was absent 2. We and others have shown that IDH1/2 mutations sensitise glioma and colorectal carcinoma cells to therapies that involve oxidative stress, such as radiotherapy, cisplatin and carmustine 16 34 35. Combined, these data suggest that at least some types of cancer with IDH1/2 mutations should be targeted by compounds that exploit this presumed metabolic vulnerability rather than compounds that decrease metabolic stress (ie, IDH1/2-mutant inhibitors).…”

“…More specifically, D -2HG inhibits enzymatic activity of complex IV (cytochrome C oxidase) of the ETC27 and the TCA(-like) enzymes IDH1/2 and αKG dehydrogenase 16. This reduces oxidative phosphorylation, the primary source of ATP in cancer cells 27 28.…”

“…To summarise, fundamental and translational research by us and others revealed that IDH1/2 mutations impart therapeutically targetable metabolic vulnerabilities to cells from several types of cancer 16 20 21 27 28. We aim to use these metabolic alterations in IDH1/2 -mutated tumours for screening purposes and tumour response monitoring purposes using non-invasive modalities.…”

Isocitrate dehydrogenase 1 and 2 genes mutations and MGMT methylation in gliomas

“…Кроме этого, в экспериментах с культурами кле-ток было продемонстрировано, что клетки, содер-жащие мутантные IDH1 / 2, обладают повышенными радиочувствительностью и чувствительностью к химио-препаратам, что, по-видимому, связано с нарушением ответа на окислительный стресс [12][13][14]. Увеличение чувствительности глиом с мутантными IDH1 / 2 к ра-дио-и химиотерапии также было показано и в клини-ческих исследованиях [15,16].…”