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

Abstract

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.

• Authors: Mark A Gregory, Angelo D'Alessandro, Francesca Alvarez-Calderon, Jihye Kim, Travis Nemkov, Biniam Adane, Andrii I Rozhok, Amit Kumar, Vijay Kumar, Daniel A Pollyea, Michael F Wempe, Craig T Jordan, Natalie J Serkova, Aik Choon Tan, Kirk C Hansen, James DeGregori
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 43 Pg. E6669-E6678 (10 25 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27791036 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzothiazoles
• Hydrazines
• Phenylurea Compounds
• Protein Kinase Inhibitors
• RNA, Small Interfering
• elesclomol
• quizartinib
• Glucosephosphate Dehydrogenase
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, genetics, metabolism)
• Benzothiazoles (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Drug Therapy, Combination
• Female
• Gene Expression Regulation, Leukemic
• Glucosephosphate Dehydrogenase (antagonists & inhibitors, genetics, metabolism)
• Humans
• Hydrazines (pharmacology)
• Leukemia, Myeloid, Acute (drug therapy, genetics, mortality, pathology)
• Mice, Inbred NOD
• Middle Aged
• Oxidation-Reduction
• Phenylurea Compounds (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Survival Analysis
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, genetics, metabolism)