FLT3

Fms-like tyrosine kinase 3 (FLT3), also known as CD135, is a member of the class III family of receptor tyrosine kinases, including platelet-derived growth factor receptors α and β, c-kit and fms (PMID: 25992210). The general structure consists of five extracellular immunoglobin-like domains, a single transmembrane domain, a short juxtamembrane region and an interrupted kinase domain. FLT3 expression is limited primarily to primitive hematopoietic stem/progenitor cells and dendritic cells, FLT3 ligand (FLT3L) is secreted by bone marrow stromal stem cells and other cells, and promotes proliferation of stem cells, progenitor cells, and dendritic nuclear natural killer cells in collaboration with other growth factors. It plays roles in the processes of differentiation, survival and proliferation. The kinase activity of FLT3 is normally stimulated upon binding of FLT3 ligand (FL), which leads to receptor dimerization, autophosphorylation, and phosphorylation of other signaling proteins (PMID: 25992210, PMID: 8618433), which leads to activation of downstream signaling cascades, including signal transducers of activation and transcription (STATs), mitogen-activated protein kinases (MAP kinases) and phosphatidyl inositol-3 kinase/AKT pathways. Mutation of FLT3 induces constitutive kinase activation which is independent of ligand and occurs in about one-third of AML cases (PMID: 8618433, PMID: 10194124). About 20-25% of AML patients express FLT3 mutations as in-frame internal tandem duplications (ITDs) of varying length in the juxtamembrane domain. An additional 7-10% of patients harbor point mutations of the kinase domain activation loop (AL) or other areas. Point mutations within the juxtamembrane domain of FLT3 have also been detected and represent a rarer class of activating mutations . The crystal structure of FLT3 shows that the juxtamembrane domain makes contact with the activation loop and maintains FLT3 in an autoinhibited state (PMID: 14759363, PMID: 12691136). Mutations in the juxtamembrane domain or in the activation loop destabilize the inhibitory conformation and lead to constitutive FLT3 activation. Activating mutations of FLT3 are also observed at lower frequencies in acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and mixed-lineage leukemia (MLL) rearranged infant leukemias (PMID: 10233379, PMID: 28077790, PMID: 28077790).

Multiple FLT3 inhibitors are in clinical trials for treating patients with FLT3/ITD-mutated disease. Sorafenib is an oral multikinase inhibitor of RAF-1, VEGF, c-KIT, PDGFR, ERK, and FLT3. Currently, sorafenib is approved for treating hepatocellular carcinoma and renal cell carcinoma. Sorafenib also has a potent anti-leukemic effect on FLT3-mutated AML. It completely inhibits FLT3/ITD activity (PMID: 29702736). Sunitinib (SU11248) is a small-molecule FLT3 inhibitor with selectivity for PDGFR, VEGFR1, VEGFR2, KIT, and FLT3. It has both direct anti-tumor and antiangiogenic properties. The use of sunitinib is currently approved for treating renal cell carcinoma, gastrointestinal stromal tumor, and AML (PMID: 12748309). Lestaurtinib (CEP-701) is an orally bioavailable indolocarbazole alkaloid compound derived from the bacterial fermentation product K-252a. It has activities against tropomyosin receptor kinases, neurotrophin receptors, FLT3, and JAK2, lestaurtinib is cytotoxic to human AML cell lines expressing both mutant and wild-type FLT3, and it prolongs the survival of FLT3/ITD leukemia in a mouse model (PMID: 24903629, PMID: 30668266 ). Tandutinib (MLN518, CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases, FLT3, PDGFR, and KIT. Tandutinib induces apoptosis and inhibits FLT3/ITD phosphorylation, cellular proliferation, and signaling of the MAPK and PI3K pathways (PMID: 15256420, PMID: 12124172). Midostaurin (CGP41251, PKC412) is a small-molecule tyrosine kinase inhibitor (TKI) and was approved by the US FDA in 2017 for the treatment of FLT3-mutated AML. It has recently been approved for newly diagnosed patients with FLT3-mutated AML and advanced systemic mastocytosis (PMID: 28546144). Quizartinib (AC220) is a selective and highly potent second-generation class III receptor TKI. Quizartinib is a potent and selective FLT3 inhibitor for AML (PMID: 20007803). Crenolanib is a potent and selective inhibitor of FLT3/WT, FLT3/ITD, FLT3-TKD, PDGFRα/β, KIT, and FLT3/D835. Crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than that by quizartinib (PMID: 23497317). Gilteritinib (ASP2215) is a novel dual FLT3/AXL inhibitor. Gilteritinib significantly reduced the colony-forming capacity of FLT3/ITD-positive leukemia cells (PMID: 29669779).