Radioprotection of IDH1 -Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198
Published version of a preprint
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 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.
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Inhibitors targeting mutant IDH1 can antagonize the effects of radiation therapy in glioma, suggesting that inhibiting mutant IDH could confer resistance to some therapies.
“However, some evidence suggests that inhibiting mutant IDH could confer resistance to some therapies, as inhibitors targeting mutant IDH1 can antagonize the effects of radiation therapy in glioma (Molenaar et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Molenaar et al., 2015
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References 61 · Cited by 148
- Authors
- Molenaar, R. J., Botman, D., Smits, M. A., Hira, V. V., van Lith, S. A., Stap, J., Henneman, P., Khurshed, M., Lenting, K., Mul, A. N., Dimitrakopoulou, D., van Drunen, C. M., Hoebe, R. A., Radivoyevitch, T., Wilmink, J. W., Maciejewski, J. P., Vandertop, W. P., Leenders, W. P., Bleeker, F. E., & van Noorden, C. J.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- 2Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
- Radboud University Medical Center (NL)
- 4Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
- Cleveland Clinic (US)
- 1Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
- ORCID
- Venue
- Cancer Research
- Published
- 2015-11-15
- Volume
- 75
- Issue
- 22
- Pages
- 4790-4802
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2164277652
- Cited by
- 148
- References
- 61
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 4 · 2023: 9 · 2022: 11 · 2021: 24 · 2020: 11 · 2019: 22 · 2018: 22 · 2017: 18 · 2016: 8 · 2015: 1
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Central China Normal University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- IDH1 mutation, AGI-5198, isocitrate dehydrogenase inhibitors, radiosensitivity, ionizing radiation, 2-hydroxyglutarate, NADPH production, reactive oxygen species, DNA double-strand breaks, oxidative stress, DNA hypermethylation, radiotherapy safety
- MeSH terms
- Antineoplastic Agents, Enzyme Inhibitors, Fluorescent Antibody Technique, Glioblastoma, Humans, Imidazoles, Isocitrate Dehydrogenase, Mutation, NADP, Radiation Tolerance, Blotting, Western, Oxidative Stress, DNA Methylation, Benzeneacetamides, Cell Line, Tumor, Gene Knock-In Techniques, Chemoradiotherapy, In Vitro Techniques
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