Fms-like tyrosine kinase 3 (FLT3) with F691L mutation (FLT3-F691L)

Fms-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays a critical role in the proliferation, survival, and differentiation of hematopoietic progenitor cells (UniProt P36888). The F691L mutation is a specific point mutation where phenylalanine is replaced by leucine at the gatekeeper residue of the kinase domain, a site that regulates access to the hydrophobic back pocket of the ATP-binding site (Smith et al., 2015, Nature). In clinical practice, FLT3-F691L is primarily recognized as a major mechanism of acquired resistance in patients with acute myeloid leukemia (AML) who have been treated with FLT3 inhibitors like quizartinib or gilteritinib (Tarver et al., 2020, Blood Cancer Journal). This mutation sterically hinders the binding of Type II inhibitors and reduces the sensitivity of Type I inhibitors, leading to disease relapse (Zhen et al., 2023, Journal of Hematology & Oncology). Because FLT3-F691L maintains the constitutive signaling that drives leukemogenesis, it is a high-priority target for next-generation tyrosine kinase inhibitors and combination therapies designed to overcome gatekeeper-mediated resistance (Yamaura et al., 2018, Blood).

Other names

CD135STK1FLK2FLT3 gatekeeper mutationFms-related receptor tyrosine kinase 3Fetal liver kinase 2

Tyrosine kinase inhibition via competitive binding to the ATP-binding site or stabilization of the inactive DFG-out conformation.