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

Affiliations

• PMID: 26363012
• DOI: 10.1158/0008-5472.CAN-14-3603

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

Remco J Molenaar et al. Cancer Res. 2015.

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.

Similar articles

• Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells.

  Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A, Hu G, Tinoco G, Bodamer O, Trent JC. Li L, et al. PLoS One. 2015 Sep 14;10(9):e0133813. doi: 10.1371/journal.pone.0133813. eCollection 2015. PLoS One. 2015. PMID: 26368816 Free PMC article.

• Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death.

  Mohrenz IV, Antonietti P, Pusch S, Capper D, Balss J, Voigt S, Weissert S, Mukrowsky A, Frank J, Senft C, Seifert V, von Deimling A, Kögel D. Mohrenz IV, et al. Apoptosis. 2013 Nov;18(11):1416-1425. doi: 10.1007/s10495-013-0877-8. Apoptosis. 2013. PMID: 23801081

• Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors.

  Chitneni SK, Reitman ZJ, Spicehandler R, Gooden DM, Yan H, Zalutsky MR. Chitneni SK, et al. Bioorg Med Chem Lett. 2018 Feb 15;28(4):694-699. doi: 10.1016/j.bmcl.2018.01.015. Epub 2018 Jan 12. Bioorg Med Chem Lett. 2018. PMID: 29366652 Free PMC article.

• ML309: A potent inhibitor of R132H mutant IDH1 capable of reducing 2-hydroxyglutarate production in U87 MG glioblastoma cells.

  Davis M, Pragani R, Popovici-Muller J, Gross S, Thorne N, Salituro F, Fantin V, Straley K, Su M, Dang L, Simeonov A, Shen M, Boxer MB. Davis M, et al. 2012 Apr 16 [updated 2013 May 8]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010–. 2012 Apr 16 [updated 2013 May 8]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010–. PMID: 23905201 Free Books & Documents. Review.

• Wild-type and mutated IDH1/2 enzymes and therapy responses.

  Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Molenaar RJ, et al. Oncogene. 2018 Apr;37(15):1949-1960. doi: 10.1038/s41388-017-0077-z. Epub 2018 Jan 25. Oncogene. 2018. PMID: 29367755 Free PMC article. Review.

Cited by

• Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma.

  Hoffman DI, Abdullah KG, McCoskey M, Binder ZA, O'Rourke DM, Desai AS, Nasrallah MP, Bigdeli A, Morrissette JJD, Brem S, Bagley SJ. Hoffman DI, et al. J Neurooncol. 2019 Nov;145(2):321-328. doi: 10.1007/s11060-019-03298-6. Epub 2019 Sep 21. J Neurooncol. 2019. PMID: 31542863

• The implications of IDH mutations for cancer development and therapy.

  Pirozzi CJ, Yan H. Pirozzi CJ, et al. Nat Rev Clin Oncol. 2021 Oct;18(10):645-661. doi: 10.1038/s41571-021-00521-0. Epub 2021 Jun 15. Nat Rev Clin Oncol. 2021. PMID: 34131315 Review.

• Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms.

  Kessler J, Hohmann T, Güttler A, Petrenko M, Ostheimer C, Hohmann U, Bache M, Dehghani F, Vordermark D. Kessler J, et al. Cancers (Basel). 2019 Jun 25;11(6):889. doi: 10.3390/cancers11060889. Cancers (Basel). 2019. PMID: 31242696 Free PMC article.

• Mitochondrial Redox Hubs as Promising Targets for Anticancer Therapy.

  Ippolito L, Giannoni E, Chiarugi P, Parri M. Ippolito L, et al. Front Oncol. 2020 Feb 28;10:256. doi: 10.3389/fonc.2020.00256. eCollection 2020. Front Oncol. 2020. PMID: 32185131 Free PMC article. Review.

• Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress.

  Gelman SJ, Naser F, Mahieu NG, McKenzie LD, Dunn GP, Chheda MG, Patti GJ. Gelman SJ, et al. Cell Rep. 2018 Jan 9;22(2):512-522. doi: 10.1016/j.celrep.2017.12.050. Cell Rep. 2018. PMID: 29320744 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Silverchair Information Systems

• Other Literature Sources

  • The Lens - Patent Citations Database

• Miscellaneous

  • NCI CPTAC Assay Portal