Fms-like tyrosine kinase 3 (FLT3) (FLT3)

Fms-like tyrosine kinase 3 (FLT3) is a Class III receptor tyrosine kinase that is essential for the normal development and maintenance of hematopoietic stem and progenitor cells. Upon binding its ligand, FLT3 undergoes dimerization and autophosphorylation of its intracellular kinase domain, triggering downstream signaling pathways including PI3K/AKT, MAPK/ERK, and STAT5 to promote cell survival and proliferation (UniProt P36888). In clinical oncology, FLT3 is a major therapeutic target because it is one of the most frequently mutated genes in acute myeloid leukemia (AML), occurring in approximately 30% of patients (PubMed: 29077157). These mutations, typically internal tandem duplications (ITD) or point mutations in the tyrosine kinase domain (TKD), result in constitutive, ligand-independent activation of the receptor. Drugs targeting the FLT3 kinase domain, such as midostaurin, gilteritinib, and quizartinib, act as competitive inhibitors of the ATP-binding site to shut down oncogenic signaling (StatPearls: NBK547711). Despite the success of these tyrosine kinase inhibitors, clinical challenges remain, including the emergence of secondary resistance mutations and the need for combination therapies to improve long-term outcomes (PubMed: 30335115).

Other names

CD135STK1FLK2Fetal liver kinase 2Stem cell tyrosine kinase 1

Inhibition of the intracellular tyrosine kinase domain by competing with ATP for the binding pocket, which prevents autophosphorylation and blocks downstream signaling through the PI3K, MAPK, and STAT5 pathways (PubMed: 29077157).