Table 2.

Mechanisms of resistance of FLT3-mutated AML cells to FLT3 inhibitors

Intrinsic
PrimarySecondaryExtrinsic
Lack of addiction to FLT3 signaling due to polyclonality/low FLT3 mutation allelic burden.New mutations in FLT3-ITDInduction of FLT3 ligand by chemotherapy
Resistance of FLT3 with specific mutations to specific FLT3 inhibitor(s)Genomic instabilityInduction of fibroblast growth factor 2 (FGF2)
Upregulation of Mcl-1 by FLT3-ITD627EUpregulation of Pim kinasesEnhanced CXCL12–CXCR4–mediated homing, associated with Pim-1 overexpression
Bcl-xL upregulation in FLT3-ITD-TKD dual mutant cellsActivation of AXLActivation of extracellular regulated kinase (ERK) by bone marrow stroma
FLT3-independent Bcl-2 upregulationActivation of SYKInduced hepatic metabolism of FLT3 inhibitor
  • NOTE: Primary resistance occurs before treatment, whereas secondary resistance is induced by FLT3 inhibitor therapy. Intrinsic mechanisms occur within AML cells, while extrinsic processes are external to AML cells.