Published online Sep 14, 2018. doi: 10.5306/wjco.v9.i5.90
Peer-review started: June 12, 2018
First decision: July 19, 2018
Revised: August 2, 2018
Accepted: August 6, 2018
Article in press: August 7, 2018
Published online: September 14, 2018
Processing time: 95 Days and 5 Hours
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.
Core tip: FMS-like tyrosine kinase 3 (FLT3) mutations including internal tandem duplication (ITD) or point mutation in tyrosine kinase domain are common genetic abnormalities in acute myeloid leukemia (AML), predicting dismal outcome. The Federal Drug Administration granted the use of Midostaurin (Novartis) in newly diagnosed FLT3-ITD positive AML in April 2017. A number of other FLT3 inhibitors are in different phases of clinical trials. However, emerging drug resistance poses a major challenge for clinicians to use FLT3 inhibitors. In this manuscript, we systematically reviewed mechanism of primary resistance and acquired resistance to FLT3 inhibitors. We then propose different strategies to overcome drug resistance and novel treatment options for FLT3-ITD positive AML.