“FLipping” the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors

Abstract

The treatment of many types of cancers, including acute myeloid leukemia (AML), has been revolutionized by the development of therapeutics targeted at crucial molecular drivers of oncogenesis. In contrast to broad, relatively indiscriminate conventional chemotherapy, these targeted agents precisely disrupt key pathways within cancer cells. FMS-like tyrosine kinase 3 (FLT3)—encoding a critical regulator of hematopoiesis—is the most frequently mutated gene in patients with AML, and these mutations herald reduced survival and increased relapse in these patients. Approximately 30% of newly diagnosed AML carries an FLT3 mutation; of these, approximately three-quarters are internal tandem duplication (ITD) mutations, and the remainder are tyrosine kinase domain (TKD) mutations. In contrast to its usual, tightly controlled expression, FLT3-ITD mutants allow constitutive, “run-away” activation of a large number of key downstream pathways which promote cellular proliferation and survival. Targeted inhibition of FLT3 is, therefore, a promising therapeutic avenue. In April 2017, midostaurin became both the first FLT3 inhibitor and the first targeted therapy of any kind in AML to be approved by the US FDA. The use of FLT3 inhibitors has continued to grow as clinical trials continue to demonstrate the efficacy of this class of agents, with an expanding number available for use as both experimental standard-of-care usage. This review examines the biology of FLT3 and its downstream pathways, the mechanism of FLT3 inhibition, the development of the FLT3 inhibitors as a class and uses of the agents currently available clinically, and the mechanisms by which resistance to FLT3 inhibition may both develop and be overcome.

Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways

“…FLT3 is a class-3 tyrosine kinase receptor that is usually expressed in marrow stromal and hematopoietic cells and plays an important role in hematopoietic cell maturation and proliferation [28]. Upon binding to its ligand, FLT3 undergoes homodimerization and conformational changes, which lead to its autophosphorylation and activation [3]. After ligand binding, the dimerized activated receptor is rapidly internalized and degraded [3].…”

“…Thus, exploration of new treatment strategies is urgently needed for patients, especially those with unfavorable genetic or chromosomal high-risk factors. Approximately one-third of newly diagnosed patients with AML carry mutations in the gene that encodes the receptor of Fms-like tyrosine kinase 3 (FLT3) [3]; approximately 75% of those harbor internal tandem duplication (ITD) mutations, while the remainder harbor tyrosine kinase domain (TKD) mutations [3]. Although FLT3-TKD mutations have a limited influence on the prognosis of patients with AML, FLT3-ITD mutations are associated with poor long-term outcomes even after allogeneic hematopoietic stem cell transplantation [4,5].…”

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

“…A paradigmatic example is FLT3, a receptor tyrosine kinase able to translate external stimuli into pro-proliferative signaling cascades. It consists of five immunoglobulin-like domains in the extracellular region, a juxtamembrane (JM) domain, a TK domain separated by a kinase insert domain and a C-terminal domain in the intracellular region [ 2 ]. The binding of the ligand to the FLT3 receptor has an important role in the regulation of cell proliferation, differentiation and survival through various signaling pathways, including RAS/mitogen-activated protein kinases (RAS/MAPK), Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) [ 3 ] ( Figure 1 A).…”

The importance of molecular diagnostic techniques on evaluation of cancers

“…It is noteworthy that during the last several years, researchers have created drugs intended to block FLT3, and some are now undergoing clinical trials. If these drugs are effective, the existence of FLT3 changes, as identified by a molecular diagnostic, may help predict how well a patient would respond to therapy [4]. Another component of prognosis that molecular diagnostics may assess is the probability that cancer will return after therapy.…”