Resistance to FLT3 inhibitors in acute myeloid leukemia: Molecular mechanisms and resensitizing strategies

Abstract

FMS-like tyrosine kinase 3 (FLT3) is classified as a type III receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia (AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.

Keywords: Acute myeloid leukemia; Combination therapy; Drug resistance; FLT3 inhibitor; FMS-like tyrosine kinase 3; Internal tandem duplication; Tyrosine kinase domain.

Figure 1

Schematic representation of various published mechanisms of resistance to FMS-like tyrosine kinase 3 inhibitors. This figure shows a number of models of resistance including desensitization of drug targets by FLT3 gene amplification or protein overexpression, decreased drug binding affinity by mutation, deletion or insertion in TKD, increased drug efflux by p-gp, activation of survival and proliferative pathways (molecules) such as RAS pathway, STAT pathway, anti-apoptotic Bcl-xL, Survivin and DNA repair molecule RAD51. FLT3: FMS-like tyrosine kinase 3; TKD: Tyrosine kinase domain; STAT: Signal transducer and activator of transcription.