Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (26363012)
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.
Journal Cancer research
Vol 75
Issue 22
Date 2015 Nov 15
URL
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

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 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
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 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