Causative Factors Involved in Development of Resistance to Tyrosine Kinase Inhibition and Novel Strategies Designed to Override This Resistance

This article describes original work performed in our laboratory related to the characterization of kinase inhibitors developed to treat myeloid leukemia, as well as identified mechanisms that likely contribute to resistance to kinase inhibition. Specifically, we provide detailed overviews of the kinase inhibitors nilotinib, used in the treatment of chronic myeloid leukemia (CML) and midostaurin, which is currently under investigation in late stage clinical trials for the treatment of mutant FLT3-positive acute myeloid leukemia (AML). Presented as well is a description of studies investigating strategies that leukemic cells employ to escape killing through kinase inhibition, including alterations in the expression and composition of targeted proteins and chemoresistance conferred by the bone marrow microenvironment. We provide a general overview of kinase inhibitors in preclinical and clinical development for CML and AML, and also discuss the use of combination therapy as an approach to enhancing the efficacy of tyrosine kinase inhibition and reducing the incidence of residual disease.