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Momelotinib is a highly potent inhibitor of FLT3-mutant AML
Mohammad Azhar1, Zachary Kincaid1, Meenu Kesarwani1
1Division of Pathology, Cincinnati Children's Hospital, Cincinnati, OH.
Abstract:
Despite the introduction of more selective FLT3 inhibitors to treat FLT3-mutated acute myeloid leukemia (AML), remissions are short lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are 2 principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical response. Here, we show that the JAK2 inhibitor momelotinib is an equipotent type 1 FLT3 inhibitor. Momelotinib showed potent inhibition of FLT3-internal tandem duplication in mouse and human primary cells and effectively suppressed its clinically relevant resistant variants within the activation loop at residues D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by growth factors and hematopoietic cytokine-activated JAK2 signaling. Consequently, concomitant inhibition of FLT3 and suppression of growth factor signaling by momelotinib treatment showed better efficacy in suppressing leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type 1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response and, thus, warrants its clinical evaluation.
Insights
Momelotinib, a JAK2 inhibitor, also targets FLT3 mutations in acute myeloid leukemia (AML). This dual inhibition overcomes resistance mechanisms, offering potential for deeper, durable responses in AML patients.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- FLT3-mutated acute myeloid leukemia (AML) often shows short remissions and rapid relapse despite targeted therapies.
- Mechanisms of relapse include resistance-conferring mutations and growth factor signaling.
- Dual inhibition strategies targeting both FLT3 and resistance pathways are needed for improved clinical outcomes.
Purpose of the Study:
- To investigate momelotinib, a JAK2 inhibitor, as a potential dual inhibitor of FLT3 and associated resistance pathways.
- To evaluate momelotinib's efficacy against FLT3 mutations and its impact on growth factor signaling in AML.
Main Methods:
- Assessed momelotinib's inhibitory activity against FLT3-internal tandem duplication (ITD) and resistant variants (D835, D839, Y842) in murine and human AML cells.
- Evaluated momelotinib's effect on JAK2 signaling and growth factor-mediated resistance.
- Tested momelotinib's efficacy in a preclinical murine model of AML.
Main Results:
- Momelotinib demonstrated equipotent type 1 FLT3 inhibition, effectively suppressing FLT3-ITD and its resistant mutants.
- Momelotinib suppressed resistance mediated by growth factors and hematopoietic cytokine-activated JAK2 signaling.
- Combined FLT3 and JAK2 inhibition by momelotinib showed enhanced efficacy in suppressing AML in vivo.
Conclusions:
- Momelotinib acts as a dual JAK2/FLT3 inhibitor, offering a potential alternative to existing therapies like gilteritinib.
- Its ability to overcome FLT3 resistance mutations and suppress growth factor signaling suggests potential for durable responses.
- Clinical evaluation of momelotinib for FLT3-mutated AML is warranted.
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