Figure 3.

Resistant mechanism of FLT3 inhibitors. A, On–target resistance of FLT3 inhibitors. To date, several activating FLT3 mutations have been identified in acute myeloid leukemia (AML) cells. During the treatment with FLT3 inhibitors, additional mutations in the FLT3 gene are acquired. Although the potencies of FLT3 inhibitors against each acquired mutation are different, those against the gatekeeper mutation, F691L, are low. B, In the culture medium, most FLT3 inhibitors exist as free‐forms, and inhibit the proliferation of mutant FLT3‐expressing cells. C, Binding to plasma proteins, such as AGP, reduce the free‐inhibitor concentration in blood. The bone marrow microenvironment is associated with a primary resistant mechanism. D, FL reduces the inhibitory activity of FLT3 inhibitors through the activation of Wt‐FLT3. E, FGF2 reduces the inhibitory activity of FLT3 inhibitors through the activation of FGFR1. F, CYP3A4 expressed in bone marrow stromal cells metabolizes FLT3 inhibitors. G, Other gene mutations, particularly RAS/MAPK pathway gene mutations, confer resistance during treatment with FLT3 inhibitors. AGP, acid‐α‐glycoprotein; BM, bone marrow; EC, extra‐cellular; FL, FLT3 ligand; JM, juxtamembrane; PB, peripheral blood; TK, tyrosine kinase