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TheScientificWorldJOURNAL
Volume 6 (2006), Pages 918-930
http://dx.doi.org/10.1100/tsw.2006.184
Review Article

Treating Imatinib-Resistant Leukemia: The Next Generation Targeted Therapies

1Molecular Biology Institute, University of California, Los Angeles, CA, USA
2Howard Hughes Medical Institute, University of California, Los Angeles, CA, USA
3Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Received 29 August 2005; Revised 28 July 2006; Accepted 31 July 2006

Academic Editor: Edward J. Benz

Copyright © 2006 Michael R. Burgess and Charles L. Sawyers.

Abstract

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.