Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors

Remco J. Molenaar, Tomas Radivoyevitch, Yasunobu Nagata, Mohammed Khurshed, Bartolomiej Przychodzen, Hideki Makishima, Mingjiang Xu, Fonnet E. Bleeker, Johanna W. Wilmink, Hetty E. Carraway, Sudipto Mukherjee, Mikkael A. Sekeres, Cornelis J.F. van Noorden, Jaroslaw P. Maciejewski

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2 MUT 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 IDH1/2 MUT AML is not known. Experimental Design: Well-characterized primary IDH1 MUT , IDH2 MUT , and IDH1/2 WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors. Results: IDH1/2 MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2 MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2 MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2 MUT 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 IDH1/2 MUT cells. Conclusions: IDH1/2 MUT 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 IDH1/2 MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2 MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2 MUT AML.

Original languageEnglish (US)
Pages (from-to)1705-1715
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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