Research ArticleCancer

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

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Science Translational Medicine  01 Feb 2017:
Vol. 9, Issue 375, eaal2463
DOI: 10.1126/scitranslmed.aal2463

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Target 2HG or not 2HG, that is the question

Mutations in isocitrate dehydrogenase 1 and 2, which result in overproduction of 2-hydroxyglutarate (2HG), are observed in multiple tumor types, including gliomas and acute myelogenous leukemia. An additional form of 2HG is produced under hypoxia, which is also frequent in tumors. 2HG is considered to be an oncometabolite, or a metabolite that promotes carcinogenesis, and inhibitors of mutant isocitrate dehydrogenase are in development to target this process. However, Sulkowski et al. found that it may be possible to take advantage of 2HG overproduction instead. The authors discovered that 2HG overproduction impairs homologous recombination used in DNA repair and sensitizes cancer cells to treatment with PARP inhibitors, another class of cancer drugs that are already in clinical use.

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