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

SIMPLE SUMMARY: Patients with acute myeloid leukemia (AML) may have a number of different mutations. Those with mutations in the FLT3 gene have a higher risk of relapse and death than those lacking these mutations. FLT3 is a key receptor on the surface of AML cells, which drives cell survival and growth. Although activation of this receptor is normally tightly controlled, in AML, FLT3 mutations allow it to activate itself, independent of external control. Over the past 5 years, a number of new drugs have been developed to specifically target these mutations. In this article, we discuss these drugs and their uses, as well as the mechanisms by which AML cells may gain resistance to them and how that resistance can be overcome. 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.