Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

Abstract

The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30⁻35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a 'dual mutation' (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.

Keywords: FLT3; acute myeloid leukemia; resistance; tyrosine kinase inhibitors.

Figure 1

Domains and AML-associated mutations of the FLT3 receptor tyrosine kinase. The FLT3 kinase is a 993 amino acid protein comprised of extracellular, transmembrane, juxtamembrane, and split kinase domains. Mutations which have been reported in AML are notated on the right-hand side of the figure. Figure created using data from references [11,14,20,21,22,23,24,25,26,27,28,29].

Figure 2

Canonical FLT3 and mutant FLT3 signaling pathways. Similar and divergent signaling pathways of wild-type and mutant FLT3 identified by functional genomic studies and large scale proteomic profiling experiments. (A) Upon binding of the FLT3 ligand (FLT3L), the FLT3 receptor undergoes a change in conformation and trans-autophosphorylation. (B) FLT3-ITD, (C) FLT3-TKD and (D) FLT3-ITD-TKD dual mutations lead to constitutive, ligand independent activation of the FLT3 receptor. Subsequent recruitment of adaptor proteins effects the activation of downstream kinase signaling pathways, such as MAPK, JAK-STAT, and PI3K. Coloring indicates activation of pathway phosphorylation or expression changes associated with the wild-type and mutant FLT3 receptor forms. Numbers indicate amino acid residues of the human protein sequence. Figure created using data from references [18,72,99,100,101,102,103,104,105,106,107,108,109,110].

Figure 3

Kinase targets of first- and second-generation FLT3 inhibitors. Kinase trees depicting the dissociation constant (Kd, (nM)) of the target kinases of each inhibitor. Size of red bubble is proportional to the Kd value, with a larger bubble indicating a lower Kd. First generation inhibitors = 1st, second generation inhibitors = 2nd. Brackets indicate whether the inhibitor is type I or type II. Illustrations reproduced Courtesy of Cell Signaling Technology, created using KinMap [138], with data from references [139,140,141].