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

Area of Science:

• Oncology
• Hematology
• Cancer Metabolism

Background:

• Acute myeloid leukemia (AML) with FLT3-ITD mutations presents a high risk of relapse and poor survival.
• Gilteritinib is a tyrosine kinase inhibitor used for FLT3-mutated AML, but its full mechanism requires elucidation.
• Identifying novel therapeutic targets is crucial to enhance gilteritinib's efficacy.

Purpose of the Study:

• To uncover additional therapeutic targets for FLT3-ITD AML to augment gilteritinib's antileukemic activity.
• To investigate the role of glutamine transporter SNAT1 (SLC38A1) as a novel target of gilteritinib.

Main Methods:

• Unbiased transcriptomic analysis to identify novel targets.
• Metabolomics and metabolic flux analysis to assess glutamine metabolism.
• Ex vivo studies using primary FLT3-ITD AML cells treated with gilteritinib and CB-839.

Main Results:

• Gilteritinib targets SNAT1 (SLC38A1), reducing glutamine uptake and TCA cycle metabolism.
• Treatment decreased 2-hydroxyglutarate, ATP, and glutathione, while increasing reactive oxygen species, inducing senescence.
• The glutaminase inhibitor CB-839 potentiated gilteritinib's antileukemic effects in FLT3-ITD AML cells.

Conclusions:

• Gilteritinib disrupts a critical metabolic pathway involving SNAT1, impacting glutaminolysis and redox balance.
• Targeting SNAT1 and glutaminolysis offers a potential therapeutic strategy for FLT3-ITD AML.
• Combinatorial therapy with gilteritinib and glutaminase inhibitors warrants further investigation for relapse/refractory AML.