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|Ref Type||Journal Article|
|Authors||Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, Henneman P, Khurshed M, Lenting K, Mul AN, Dimitrakopoulou D, van Drunen CM, Hoebe RA, Radivoyevitch T, Wilmink JW, Maciejewski JP, Vandertop WP, Leenders WP, Bleeker FE, van Noorden CJ|
|Title||Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198.|
|Date||2015 Nov 15|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|IDH1 R132H||colorectal cancer||sensitive||Metformin||Preclinical||Actionable||In a preclinical study, colorectal carcinoma cells expressing IDH1 R132H were sensitive to Glucophage (metformin), resulting in decreased cell proliferation in culture (PMID: 26363012).||26363012|
|IDH1 R132H||colorectal cancer||resistant||AGI-5198 + Radiotherapy||Preclinical||Actionable||In a preclinical study, colorectal cancer cells expressing IDH1 R132H were resistant to radiotherapy when treated with AGI-5198 (PMID: 26363012).||26363012|
|IDH1 R132H||colorectal cancer||resistant||AGI-5198 + Metformin||Preclinical||Actionable||In a preclinical study, colorectal cancer cells harboring IDH1 R132H demonstrated increased cell proliferation when treated with a combination of Glucophage (metformin) and AGI-5198 (PMID: 26363012).||26363012|