Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma
Scanlon SE, Hegan DC, Sulkowski PL, Glazer PM. Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget 2017, 9: 4647-4660. PMID: 29435132, PMCID: PMC5797003, DOI: 10.18632/oncotarget.23470.Peer-Reviewed Original ResearchDouble-strand break repairDNA double-strand break repairBreak repairHomologous recombinationHomology-dependent DNA double-strand break repairGene expressionHuman clear cell renal carcinomaHuman renal cell carcinomaVon Hippel-Lindau (VHL) tumor suppressor geneDNA double-strand breaksDNA repair gene expressionHr gene expressionRadiation-induced DNA double-strand breaksImpaired DNA double-strand break repairPro-growth stateDouble-strand breaksDNA repair genesRepair gene expressionDNA repair defectsTumor suppressor genePARP inhibitor sensitivityRenal cancer cellsTranscriptional reprogrammingGene repressionRenal carcinoma samples2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
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. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Science Translational Medicine 2017, 9 PMID: 28148839, PMCID: PMC5435119, DOI: 10.1126/scitranslmed.aal2463.Peer-Reviewed Original ResearchConceptsIsocitrate dehydrogenase 1PARP inhibitor sensitivityPossible therapeutic strategiesHomologous recombination defectsTherapeutic strategiesTumor xenograftsInhibitor sensitivityPathologic processesSmall molecule inhibitorsIDH1/2 mutationsTumor progressionIDH2 mutationsMutant IDHPolymerase inhibitorsGlioma cellsTumor cellsHR deficiencyPARP inhibitionIDH mutationsInhibitory effectDehydrogenase 1Neomorphic activityMutant IDH1 enzymeDependent dioxygenasesMutant cells