Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells. Although significant progress has been made in treating many types of cancers during recent years, AML remains a deadly disease with survival rate lagging behind other blood cancers. A combination of toxic chemotherapies has been the standard AML treatment for more than 40 years. With intensive efforts to define the pathogenesis of AML, novel therapeutic drugs targeting key molecular defects in AML are being developed. Mutated in nearly 30% of AML, FMS-like tyrosine kinase 3 (FLT3) represents one of the most attractive targets. FLT3 mutants resulted from either internal tandem duplication (ITD) or point mutations possess enhanced kinase activity and cause constitutive activation of signaling. To date, several small molecule inhibitors of FLT3 have been developed but their clinical efficacy is limited due to a lack of potency and the generation of drug resistance. Therefore, next-generation FLT3 inhibitors overcoming these limitations are urgently in need. This review focuses on the pathological role of mutant FLT3 in the development of AML, the current status of FLT3 inhibitor development, and mechanisms underlining the development of resistance to existing FLT3 inhibitors.

Keywords: FMS-like tyrosine kinase 3 (FLT3); Leukemia; tyrosine kinase inhibitors (TKIs).

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1

The domain structure of FLT3. The extracellular domain contains five Ig-like domains. Following the transmembrane domain (TM), the intracellular domain contains the juxtamembrane domain (JM) and the kinase domain that is divided into two parts by the kinase insert domain (KID).

Figure 2

FLT3 signaling pathway. The figure shows the downstream signaling occurs after activation of FLT3. Binding of FLT3 ligand (FLT3L) to FLT3 triggers the dimerization, followed by the activation of the JAK-STAT pathway, the PI3K pathway and the MAPK pathway. These pathways lead to increased cell proliferation/survival and the inhibition of apoptosis.

Figure 3

Locations of activating mutations of FLT3. Internal tandem duplication (ITD) occurs in exons 14 or 15 of the JM domain. Point mutations are found in exon 20 of the kinase domain.