Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.

Keywords: AML; Drug resistance; Drug tolerance; FLT3.

Fig. 1

Schematics illustrating a monomeric FLT3. Glycosylated FLT3 is anchored on the plasma membrane (PM) with the transmembrane domain (TM), and its immunoglobulin-like ligand binding domain protrudes out to the extracellular domain (ECD). In the cytoplasm (CP), the juxtamembrane domain (JM) extends and connects with the two kinase domain lobes (TK1 and TK2) that are linked by the activation loop (AL)