ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Abstract

<p id="d6445800e492">FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown impressive activity in clinical trials for acute myeloid leukemia (AML); however, these inhibitors invariably fail to achieve sustained remissions. Here we demonstrate that FLT3 inhibition causes severe deficiencies in redox metabolism and accumulation of reactive oxygen species (ROS) in the mitochondria of AML cells. We discovered that the metabolic regulators ataxia telangiectasia mutated and glucose 6-phosphate dehydrogenase help maintain antioxidant capacity and survival of a subpopulation of AML cells in the face of FLT3 inhibition. Inactivation of these factors escalates mitochondrial ROS and enhances AML cell eradication. Importantly, we show that the use of a drug that increases mitochondrial ROS enhances the efficacy of FLT3 inhibitor therapy, suggesting a combinatorial therapeutic strategy. </p><p class="first" id="d6445800e495">Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML. </p>