Abstract
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.
Highlights
Acute myeloid leukemia (AML) is a clonal disease of hematopoietic progenitor cells that are unable to differentiate [1]
Since SEL24-B489 inhibits fms-like tyrosine kinase 3 (FLT3) mutants and simultaneously blocks activity of proximally (FLT3ITD) and distally (PIMs) kinases, we hypothesized that these properties should lead to broader toxicity of the compound against acute myeloid leukemia patients (AML) cells in comparison to selective www.oncotarget.com
Since PIM kinases emerge as important mediators of FLT3-induced signaling, these findings highlight the potential clinical benefits of dual inhibitor activity (Figure 5)
Summary
Acute myeloid leukemia (AML) is a clonal disease of hematopoietic progenitor cells that are unable to differentiate [1]. AML is a heterogeneous disease, harboring numerous cytogenetic and/or submicroscopic lesions that determine disease aggressiveness Some of these lesions have been credentialed as potential therapeutic targets, but despite these discoveries, little progress in clinical outcome has been achieved in AML patients over the last decade. FLT3 is a type 3 receptor tyrosine kinase, which in non-pathological conditions is expressed on hematopoietic stem cells, but lost upon their maturation [4, 5]. In AML bearing FLT3-ITD mutations, PIM1 and PIM2 were identified as STAT5 downstream targets and mediators of increased blast survival and clonogenic potential [9, 11]. Consistent with this, ectopic PIM2 expression induced resistance to FLT3 inhibition in both FLT3-ITD–induced myeloproliferative neoplasm and AML models in mice [22], underscoring the role of PIMs in the emergence of this phenotype
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