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

Abstract

<b>Purpose:</b> Somatic mutations in <i>IDH1/2</i> occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2^MUT enzymes produce <i>D</i>-2-hydroxyglutarate (<i>D</i>2HG), 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 <i>IDH1/2</i>^MUT AML is not known.<b>Experimental Design:</b> Well-characterized primary <i>IDH1</i>^MUT, <i>IDH2</i>^MUT, and <i>IDH1/2</i>^WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors.<b>Results:</b><i>IDH1/2</i>^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 <i>IDH1/2</i>^MUT AML cells. We provide evidence that the therapy sensitivity of <i>IDH1/2</i>^MUT cells was caused by <i>D</i>2HG-mediated downregulation of expression of the DNA damage response gene <i>ATM</i> and not by altered redox responses due to metabolic alterations in <i>IDH1/2</i>^MUT cells.<b>Conclusions:</b><i>IDH1/2</i>^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 <i>IDH1/2</i>^MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in <i>IDH1/2</i>^MUT AML. <i>Clin Cancer Res; 24(7); 1705-15. ©2018 AACR</i>.