Reference Detail

Ref Type

Journal Article

PMID

(29339439)

Authors

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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	7	2018 04 01	1705-1715	Clin Cancer Res

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH2 mutant	acute myeloid leukemia	predicted - sensitive	Talazoparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells from a patient with acute myeloid leukemia harboring an IDH2 mutation were sensitive to treatment with Talzenna (talazoparib) in culture, demonstrating decreased colony formation (PMID: 29339439).	29339439
IDH1 mutant	acute myeloid leukemia	predicted - sensitive	Daunorubicin + Talazoparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination therapy of Talzenna (talazoparib) and Cerubidine (daunoruibicin) resulted in an additive effect in cells from a patient with acute myeloid leukemia harboring an IDH1 mutation, demonstrating decreased colony formation in culture (PMID: 29339439).	29339439
IDH2 mutant	acute myeloid leukemia	predicted - sensitive	Olaparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells from a patient with acute myeloid leukemia harboring an IDH2 mutation were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased colony formation (PMID: 29339439).	29339439
IDH1 R132H	colorectal cancer	predicted - sensitive	Talazoparib	Preclinical - Cell culture	Actionable	In a preclinical study, colorectal cancer cells harboring IDH1 R132H were sensitive to treatment with Talzenna (talazoparib) in culture, demonstrating decreased colony formation (PMID: 29339439).	29339439
IDH2 mutant	acute myeloid leukemia	predicted - sensitive	Daunorubicin + Olaparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination therapy of Lynparza (olaparib) and Cerubidine (daunoruibicin) resulted in an additive effect in cells from a patient with acute myeloid leukemia harboring an IDH2 mutation, demonstrating decreased colony formation in culture (PMID: 29339439).	29339439
IDH1 mutant	acute myeloid leukemia	predicted - sensitive	Talazoparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells from a patient with acute myeloid leukemia harboring an IDH1 mutation were sensitive to treatment with Talzenna (talazoparib) in culture, demonstrating decreased colony formation (PMID: 29339439).	29339439
IDH2 mutant	acute myeloid leukemia	predicted - sensitive	Daunorubicin + Talazoparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination therapy of Talzenna (talazoparib) and Cerubidine (daunoruibicin) resulted in an additive effect in cells from a patient with acute myeloid leukemia harboring an IDH2 mutation, demonstrating decreased colony formation in culture (PMID: 29339439).	29339439
IDH1 mutant	acute myeloid leukemia	predicted - sensitive	Olaparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells from a patient with acute myeloid leukemia harboring an IDH1 mutation were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased colony formation (PMID: 29339439).	29339439
IDH1 R132H	colorectal cancer	predicted - sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, colorectal cancer cells harboring IDH1 R132H were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased colony formation (PMID: 29339439).	29339439
IDH1 mutant	acute myeloid leukemia	predicted - sensitive	Daunorubicin + Olaparib	Preclinical - Patient cell culture	Actionable	In a preclinical study, the combination therapy of Lynparza (olaparib) and Cerubidine (daunoruibicin) resulted in an additive effect in cells from a patient with acute myeloid leukemia harboring an IDH1 mutation, demonstrating decreased colony formation in culture (PMID: 29339439).	29339439