Mechanisms of resistance to FLT3 inhibitors.
The success of the small molecule tyrosine kinase receptor inhibitor (TKI) imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia (CML) constitutes an eminent paradigm shift advocating the rational design of cancer therapeutics specifically targeting the transformation events that drive tumorigenicity. In acute myeloid leukemias (AMLs), the most frequent identified transforming events are activating mutations in the FLT3 receptor tyrosine kinase that constitutively activate survival and proliferation pathways. FLT3 TKIs that are in various phases of clinical trials are showing some initial promise. However, primary and secondary acquired resistance stands to severely compromise long-term and durable efficacy of these inhibitors as a therapeutic strategy. Here, we discuss the mechanisms of resistance to FLT3 inhibitors and possible strategies to overcome resistance through closer examination of the events of leukemogenesis and design of combination therapy.
Chu
S Haihua
SH
Department of Oncology, Johns Hopkins University School of Medicine, CRB1-251, 1650 Orleans St., Baltimore, MD 21231-1000, USA.
Small
Donald
D
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3