Reference Detail

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 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 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 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 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 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	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	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	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	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
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 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 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 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