Gilteritinib Inhibits Glutamine Uptake and Utilization in FLT3 -ITD–Positive AML

作者：Megan E. Zavorka Thomas, Xiyuan Lu, Zahra Talebi, Jae Yoon Jeon, Daelynn R. Buelow, Alice A. Gibson, Muhammad Erfan Uddin, Lindsey T. Brinton, Julie P. T. Nguyen, Meghan Collins, Alessia Lodi, Shannon Sweeney, Moray J. Campbell, Douglas H. Sweet, Alex Sparreboom, Rosa Lapalombella, Stefano Tiziani, Sharyn D. Baker · 发表于：Molecular Cancer Therapeutics · 年份：2021 · DOI：10.1158/1535-7163.mct-21-0071 · 被引用次数：46 · 研究领域：Acute Myeloid Leukemia Research、Epigenetics and DNA Methylation、Cancer, Hypoxia, and Metabolism

Abstract Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy associated with frequent relapse and poor overall survival. The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet its mechanism of action is not completely understood. Here, we sought to identify additional therapeutic targets that can be exploited to enhance gilteritinib's antileukemic effect. Based on unbiased transcriptomic analyses, we identified the glutamine transporter SNAT1 (SLC38A1) as a novel target of gilteritinib that leads to impaired glutamine uptake and utilization within leukemic cells. Using metabolomics and metabolic flux analyses, we found that gilteritinib decreased glutamine metabolism through the TCA cycle and cellular levels of the oncometabolite 2-hydroxyglutarate. In addition, gilteritinib treatment was associated with decreased ATP production and glutathione synthesis and increased reactive oxygen species, resulting in cellular senescence. Finally, we found that the glutaminase inhibitor CB-839 enhanced antileukemic effect of gilteritinib in ex vivo studies using human primary FLT3-ITD–positive AML cells harboring mutations in the enzyme isocitrate dehydrogenase, which catalyzes the oxidative decarboxylation of isocitrate, producing α-ketoglutarate. Collectively, this work has identified a previously unrecognized, gilteritinib-sensitive metaboli...