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

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.
Remco J Molenaar 1 2 3 4,  Tomas Radivoyevitch 5,  Yasunobu Nagata 1,  Mohammed Khurshed 2 4,  Bartolomiej Przychodzen 1,  Hideki Makishima 1,  Mingjiang Xu 6,  Fonnet E Bleeker 7 8,  Johanna W Wilmink 3 4,  Hetty E Carraway 9,  Sudipto Mukherjee 9,  Mikkael A Sekeres 1 9,  Cornelis J F van Noorden 2 4,  Jaroslaw P Maciejewski 10
Affiliations

Affiliations

  • 1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
  • 2 Department of Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 3 Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 4 Cancer Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 5 Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 6 Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida.
  • 7 Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 8 Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 9 Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
  • 10 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. maciejj@ccf.org.
PMID: 29339439 DOI: 10.1158/1078-0432.CCR-17-2796
Abstract

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.

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