Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

“…Given the successful development and utilization of numerous TKIs, the FLT3 receptor tyrosine kinase has emerged as a promising target for the treatment of AML. Indeed, activating mutations in FLT3 are one of the most frequently observed genetic defects in AML and are comprised predominantly of internal tandem duplication (ITD) mutations in the juxtamembrane domain (6). FLT3-ITD mutations are associated with poor prognosis, including increased relapse rate, decreased disease-free survival, and poor overall survival (5,7,8).…”

Expression of the Essential Kinase PfCDPK1 from Plasmodium falciparum in Toxoplasma gondii Facilitates the Discovery of Novel Antimalarial Drugs

“…PLX-4720 is a B-Raf kinase inhibitor, and its close analog vemurafenib (PLX-4032) has been approved by the FDA for use against malignant melanoma (47). The last of the inhibitors tested in P. falciparum, lestaurtinib, is a staurosporine analog that is currently in phase II clinical trials against acute myeloid leukemia (AML) caused by mutant FMS-like tyrosine kinase receptor-3 (FLT3) (48).…”

Characterization of SGN-CD123A, A Potent CD123-Directed Antibody–Drug Conjugate for Acute Myeloid Leukemia

“…Approximately 23% of AML patients carry a mutation in the FLT3 gene (20,26). Coincidentally, AML patients carrying FLT3 mutations have higher level of CD123 expression (27,28).…”

“…These patients had favorable (n ¼ 3), intermediate (n ¼ 15), or adverse (n ¼ 5) cytogenetic profiles. Fourteen of these patients also had FLT3 internal tandem duplication (FLT3/ITD), a mutation that correlates with poor prognosis in AML (20). Twenty-six percent (6/23) of patients had mutations in nucleophosmin gene (NPM1), which is associated with good prognosis in AML patients (21).…”