Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase domain mutants (FLT3-TKD)

Fms-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays a vital role in the proliferation, survival, and differentiation of hematopoietic progenitor cells (UniProt P36888). Mutations in the tyrosine kinase domain (TKD), most frequently involving point mutations at the D835 residue within the activation loop, lead to the constitutive, ligand-independent activation of the receptor (NIH Gene ID: 2322). This aberrant signaling drives the pathogenesis of approximately 7-10% of acute myeloid leukemia (AML) cases by hyperactivating downstream pathways like STAT5, MAPK/ERK, and PI3K/AKT (PubMed PMID: 32805194). Unlike internal tandem duplication (ITD) mutations, TKD mutations often confer resistance to Type II tyrosine kinase inhibitors, such as quizartinib, which require the kinase to be in an inactive conformation. Consequently, Type I inhibitors like gilteritinib and midostaurin, which can bind the active conformation, are the primary therapeutic agents used to target FLT3-TKD mutants (StatPearls: FLT3 Inhibitors). Despite these advancements, clinical challenges persist due to the emergence of secondary resistance mutations and the complex clonal architecture of the disease.

Other names

CD135FLK-2STK-1Fms-related tyrosine kinase 3FLT3-D835FLT3-I836

Type I tyrosine kinase inhibitors bind to the ATP-binding pocket of the FLT3 receptor in both active and inactive conformations, preventing autophosphorylation and blocking downstream oncogenic signaling pathways.