Strategies to overcome drug resistance in FLT3+ AML

Abstract: Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor survivalrate and limited therapeutic options. Targeted treatment of other types ofcancer, for instance chronic myeloid leukemia (CML) and breast cancer, has seensignificant progress. However, when it comes to AML, the outcome is poor witha five-year relative survival of only 20 - 30%. Over the last four years, the FDA hasapproved nine new drugs for AML patients in the United States. Unfortunately,the median overall survival of AML patients is still fairly low. For patients aged 70 years and older, the median overall survival is only about 10 months. Even forchildren with AML, the overall 5-year survival rate is 65 - 70%. A major cause oftreatment failure is the development of treatment-induced drug resistance. Thedevelopment of somatic mutations is one of the most common mechanisms ofdrug resistance.In AML, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are oftenpresent, with an incidence rate of ∼30% of cases. Most of these mutations areinternal tandem duplications (ITD), present in approximately 25% of the patients.Patients with a high FLT3-ITD burden often relapse after chemotherapy. Inpatients with FLT3-ITD mutations, FLT3 has become a promising drug target fortherapy. In the past few years, FLT3 inhibitors have led to clinical progress, butthere are still some significant problems with their usage. Among these, drugresistance is urgent to overcome.This thesis mainly focuses on exploring different treatment regimens to over-come drug resistance in human FLT3+ AML cells as a model for the disease.Initially, a drug rotation protocol between two inhibitors which have differentresistance profiles was tested. However, the results were not satisfying. Combi-nation therapy between a FLT3 inhibitor and another inhibitor was adopted. Thisstrategy exhibited significant synergy and, more importantly, could postponethe emergence of drug resistance. In further experiments, we examined somenewly-developed small molecular compounds, and it turned out some of themhad excellent inhibitory activity against established drug-resistant AML cell lines.In parallel, we have also studied the cause of resistance in these cells and haveidentified resistance mutations that have not been described before. Finally, westudied whether FLT3 inhibitors were likely to be synergistic with azacitidine, ahypomethylating agent approved for AML treatment. Such combinations did notdisplay a clear synergistic effect on AML cells, though one combination may bepromising. Overall, our studies provided a better understanding of the resistancemechanisms by which FLT3-ITD cells overcome therapy and valuable informationabout the efficacy of novel inhibitors that are not currently in clinical use, and oncombination therapies. To this end, the results will enable to further facilitatethe rational development of new strategies to overcome drug resistance in FLT3+AML.