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

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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.

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

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Acute Myeloid Leukemia
Daunorubicin
Mutation
Myeloid Cells
DNA Damage
Therapeutics
Ionizing Radiation
Oxidation-Reduction
Poly(ADP-ribose) Polymerase Inhibitors
Neoplasms
Research Design
Radiotherapy
Down-Regulation
Clinical Trials
DNA
Enzymes
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Molenaar, R. J., Radivoyevitch, T., Nagata, Y., Khurshed, M., Przychodzen, B., Makishima, H., ... Maciejewski, J. P. (2018). Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors. Clinical Cancer Research, 24(7), 1705-1715. https://doi.org/10.1158/1078-0432.CCR-17-2796

Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors. / Molenaar, Remco J.; Radivoyevitch, Tomas; Nagata, Yasunobu; Khurshed, Mohammed; Przychodzen, Bartolomiej; Makishima, Hideki; Xu, Mingjiang; Bleeker, Fonnet E.; Wilmink, Johanna W.; Carraway, Hetty E.; Mukherjee, Sudipto; Sekeres, Mikkael A.; van Noorden, Cornelis J.F.; Maciejewski, Jaroslaw P.

In: Clinical Cancer Research, Vol. 24, No. 7, 01.04.2018, p. 1705-1715.

Research output: Contribution to journalArticle

Molenaar, RJ, Radivoyevitch, T, Nagata, Y, Khurshed, M, Przychodzen, B, Makishima, H, Xu, M, Bleeker, FE, Wilmink, JW, Carraway, HE, Mukherjee, S, Sekeres, MA, van Noorden, CJF & Maciejewski, JP 2018, 'Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors', Clinical Cancer Research, vol. 24, no. 7, pp. 1705-1715. https://doi.org/10.1158/1078-0432.CCR-17-2796
Molenaar, Remco J. ; Radivoyevitch, Tomas ; Nagata, Yasunobu ; Khurshed, Mohammed ; Przychodzen, Bartolomiej ; Makishima, Hideki ; Xu, Mingjiang ; Bleeker, Fonnet E. ; Wilmink, Johanna W. ; Carraway, Hetty E. ; Mukherjee, Sudipto ; Sekeres, Mikkael A. ; van Noorden, Cornelis J.F. ; Maciejewski, Jaroslaw P. / Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 7. pp. 1705-1715.
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AU - Molenaar, Remco J.

AU - Radivoyevitch, Tomas

AU - Nagata, Yasunobu

AU - Khurshed, Mohammed

AU - Przychodzen, Bartolomiej

AU - Makishima, Hideki

AU - Xu, Mingjiang

AU - Bleeker, Fonnet E.

AU - Wilmink, Johanna W.

AU - Carraway, Hetty E.

AU - Mukherjee, Sudipto

AU - Sekeres, Mikkael A.

AU - van Noorden, Cornelis J.F.

AU - Maciejewski, Jaroslaw P.

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N2 - 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.

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