The Role of FLT3 Kinase as an AML Therapy Target

Michal      Beffinger; Anna      Skwarska

doi:10.2174/138161212800626247

Abstract

FMS-like tyrosine kinase-3 (FLT3) is a tyrosine kinase receptor involved in the survival and expansion of hematopoietic stem progenitors. A constitutively activated, mutated form of FLT3, is expressed in approximately 30% of de novo acute myeloid leukemia (AML) and about 6% of acute lymphoblastic leukemia (ALL) cases. Since mutant FLT3 has emerged as an attractive therapeutic target, there are several FLT3 inhibitors currently undergoing evaluation in different phases of clinical trials. However, although many aspects of the intracellular signaling mediated by oncogenic FLT3 have been revealed, what is the best strategy to inhibit FLT3 and how FLT3 inhibitors should be developed for AML treatment is poorly defined. Despite promising in vitro studies, where most FLT3 inhibitors show potent efficacy at nanomolar concentrations, clinical responses in AML patients are moderate and temporary. Furthermore, under prolonged therapy, FLT3 mutation-positive leukemic cells rapidly develop resistance to FLT3 inhibitors when used as monotherapy. Considering that there is no uniform mechanism of resistance triggered by FLT3 inhibitors, it will be necessary to develop new agents that target FLT3, and that can be used consecutively or in combination with conventional cytotoxic therapeutics. On the other hand, given that overexpression of FLT3 ligand (FL), occurring after myelosuppressive therapy, reduces the efficacy of FLT3 inhibitors, targeting both FL and FLT3 kinase, might be more effective approach in AML treatment. Here, we summarize up-to-date studies on FLT3 structure, its mutation status and role in malignant signal trafficking. We also review why FLT3 targeted therapies have not revolutionized AML treatment.

Keywords: Fms-like tyrosine kinase-3 (FLT3), hematopoiesis, acute myeloid leukemia (AML), receptor tyrosine kinase inhibitors, targeted therapy, acute lymphoblastic leukemia (ALL), monotherapy, cytotoxic therapeutics, myelosuppressive therapy, mutant