Journal
BLOOD ADVANCES
Volume 6, Issue 4, Pages 1186-1192Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2021004611
Keywords
-
Categories
Funding
- National Institutes of Health National Cancer Institutes [R01 CA211594, R01 CA250516]
- American Society of Hematology
Ask authors/readers for more resources
The JAK2 inhibitor momelotinib is a potent type 1 FLT3 inhibitor that effectively suppresses FLT3 mutations and growth factor signaling, showing better efficacy in suppressing leukemia in a preclinical murine model of AML.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available