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Imatinib (Glivec®) as a paradigm of targeted cancer therapies
Imatinib (Glivec®, Novartis Pharmaceuticals UK Ltd, Basel, Switzerland) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukaemia and the steps for the development of an agent to specifically inactivate this abnormality. The results of unprecedented clinical trials are reviewed alongside a description of resistance mechanisms and the development of novel tyrosine kinase inhibitors to circumvent resistance. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases is described. Finally, the application of the paradigm of targeting molecular pathogenetic events to other malignancies is explored.