Treating imatinib-resistant leukemia: the next generation targeted therapies.
Imatinib (Gleevec/STI-571/CGP57148B, Novartis) is a small-molecule, tyrosine kinase inhibitor developed to target BCR-ABL, c-Kit, and PDGF-R. Through inhibition of these oncogenic kinases, imatinib is effective in the treatment of BCR-ABL-positive leukemia, gastrointestinal stromal tumor, and hypereosinophilic syndrome, respectively. However, clinical success of imatinib is hampered by acquired resistance that may occur through several mechanisms including kinase domain mutation, target amplification, and activation of alternate signaling pathways. Strategies to overcome resistance have included targeting BCR-ABL stability and downstream signaling pathways important for tumor growth. Additional work has shown that new BCR-ABL kinase inhibitors with increased potency or alternate conformation-binding properties can target imatinib resistance. This review focuses on the mechanisms of imatinib resistance and the strategies currently being developed to overcome clinical resistance.
Burgess
Michael R
MR
Molecular Biology Institute, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, USA. mike.burgess@ucla.edu
Sawyers
Charles L
CL
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl