IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors

Clin Cancer Res. 2018 Apr 1;24(7):1705-1715. doi: 10.1158/1078-0432.CCR-17-2796. Epub 2018 Jan 16.


Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known.Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT, and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors.Results:IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells.Conclusions:IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML. Clin Cancer Res; 24(7); 1705-15. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • Daunorubicin / pharmacology
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • HCT116 Cells
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics*
  • Mutation / drug effects*
  • Mutation / genetics*
  • Oxidation-Reduction / drug effects
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism


  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • talazoparib
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Poly(ADP-ribose) Polymerases
  • olaparib
  • Daunorubicin