Molecular mechanisms of intrinsic resistance to FLT3-TKI. (A) Overview: FLT3-TKI resistance of FLT3-mutated AML can be classified in primary resistance, which is due to specific biologic characteristics of the disease, and in secondary resistance, which occurs secondarily upon exposure to TKIs. Known mechanisms of resistance to FLT3-TKIs are as follows. (B) In AML blasts expressing a mutated FLT3-receptor, survival and proliferation signals are continuously mediated by the mutant receptor. FLT3-TKIs abrogate constitutive activation of the FLT3-receptor and its downstream signals followed by apoptotic cell death. Alternatively, activation of compensatory survival pathways (eg, activating NRAS mutations) renders leukemic cells independent of FLT3. (C) Mutations in the adenosine triphosphate-binding pocket of the tyrosine-kinase domain impair binding of the TKI to the receptor. (D) Autocrine and/or paracrine FLT3-receptor stimulation via FLT3-Ligand (FL). (E) Over expression of the mutated FLT3-receptor.