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Ref Type Journal Article
PMID (28148839)
Authors Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, Bindra RS
Title 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.
Journal Vol Issue Date Pages Journal Short Title
Science translational medicine 9 375 2017 Feb 01 Sci Transl Med
URL
Abstract Text 2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-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.

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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 Advanced Solid Tumor sensitive Rucaparib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Rubraca (rucaparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132C sarcoma decreased response AGI-5198 + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, AGI-5198 reverted the sensitivity of sarcoma cells harboring IDH1 R132C to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H Advanced Solid Tumor sensitive Cisplatin + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, Talzenna (talazoparib) and Cisplatin synergistically inhibited growth of transformed cells over expressing IDH1 R132H in culture (PMID: 28148839). 28148839
IDH1 R132C sarcoma decreased response AGI-5198 + Olaparib Preclinical - Cell culture Actionable In a preclinical study, AGI-5198 reverted the sensitivity of sarcoma cells harboring IDH1 R132C to Lynparza (olaparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H colon carcinoma sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, colon carcinoma cells over expressing IDH1 R132H demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H Advanced Solid Tumor sensitive Berzosertib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing IDH1 R132H demonstrated increased sensitivity to Berzosertib (VX-970)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132C high grade glioma sensitive Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived glioma cells harboring IDH1 R132C demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H high grade glioma sensitive Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived glioma cells harboring IDH1 R132H demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Lynparza (olaparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H Advanced Solid Tumor sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132C sarcoma sensitive Olaparib Preclinical - Cell line xenograft Actionable In a preclinical study, Lynparza (olaparib) treatment delayed tumor growth in cell line xenograft models of sarcoma harboring IDH1 R132C (PMID: 28148839). 28148839
IDH1 R132H Advanced Solid Tumor decreased response AGI-5198 + Talazoparib Preclinical - Cell culture Actionable In a preclinical study, AGI-5198 reverted the sensitivity of transformed cells over expressing IDH1 R132H to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H colon carcinoma sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, colon carcinoma cells over expressing IDH1 R132H demonstrated increased sensitivity to Lynparza (olaparib)-induced growth inhibition in culture (PMID: 28148839). 28148839
IDH1 R132H Advanced Solid Tumor sensitive Niraparib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Zejula (niraparib)-induced growth inhibition in culture (PMID: 28148839). 28148839