FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

Abstract

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3-TKD). Both mutant FLT3 molecules are activated through ligand-independent dimerization and trans-phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti-apoptosis. Because high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.

Keywords: FMS-like tyrosine kinase; acute myeloid leukemia; inhibitor; resistance; tyrosine kinase.

Figure 1

History to practical use of FLT3 inhibitors. The main historical events up to the practical use of FLT3 inhibitors are demonstrated. Indicated points of FLT3 inhibitors are the start times of clinical trials

Figure 2

The frequency of FLT3 mutations and co–occurring mutations in acute myeloid leukemia (AML) patients. The frequency of FLT3 mutations and co–occurring mutations in 199 AML patients who were registered in the Japan Adult Leukemia Study Group (JALSG) AML201 study. FLT3 mutation is the most frequently identified in AML patients (A), and frequently co–occurs with NPM1, DNMT3A, IDH1/2, TET2, GATA2 and KMT2A‐partial tandem duplication mutations (B). Figures are adopted from the reference 12

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

Figure 4

Binding modes of FLT3 inhibitors to FLT3 molecule. Schematic diagrams of FLT3 kinase inhibition are shown. FLT3 inhibitors are classified into Type I and Type II inhibitors according to the mode of binding to FLT3. The Type I inhibitors bind to only the ATP‐binding site, enabling binding to both active and inactive conformations of FLT3. In contrast, because the type II inhibitors are designed to favorably bind to the back pocket of the inactive conformation of FLT3 to increase the affinity for the ATP‐binding site, they can bind to only the inactive conformation. FF‐10101 is designed to form a covalent binding between the C695 residue of FLT3. This covalent bond formation of FF‐10101 maintains the ability to bind to both the active and inactive conformations of FLT3