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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. | ||||||||||||
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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 | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 | 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 | 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 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 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 |