Author: Sulkowski, P.L.; Corso, C.D.; Robinson, N.D.; Scanlon, S.E.; Purshouse, K.R.; Bai, H.; Liu, Y.; Sundaram, R.K.; Hegan, D.C.; Fons, N.R.; Breuer, G.A.; Song, Y.; Mishra-Gorur, K.; De Feyter, H.M.; de Graaf, R.A.; Surovtseva, Y.V.; Kachman, M.; Halene, S.; Gunel, M.; Glazer, P.M.; Bindra, R.S.
Description: 2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on alpha-ketoglutarate (alphaKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitors. This “BRCAness” phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.
Subject Headings: Animals; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Repair; Female; Glioma/drug therapy/genetics; Glutarates/pharmacology; Homologous Recombination; Humans; Isocitrate Dehydrogenase/genetics/pharmacology; Mice, Nude; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology; Xenograft Model Antitumor Assays
Keywords: 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
Publication year: 2017
Journal or book title: Science Translational Medicine
Volume: 9
Issue: 375
Pages:
Find the full text : https://www.science.org/doi/abs/10.1126/scitranslmed.aal2463
Find more like this one (cited by): https://scholar.google.com/scholar?cites=17968122074800540228&as_sdt=1000005&sciodt=0,16&hl=en
Type: Journal Article
Serial number: 2580