Acquired resistance to tyrosine kinase inhibitors during cancer therapy.

Selective tyrosine kinase inhibitors have emerged as important therapeutic agents in the treatment of a variety of human malignancies. Although several of these inhibitors have marked clinical activity, it is widely recognized that the overall value of these agents is substantially limited by the acquisition of drug resistance, which eventually arises in most, if not all treated patients. Mechanisms of drug resistance are beginning to be elucidated through the molecular analysis of clinical specimens as well as through cell culture modeling. By identifying resistance mechanisms, it should be possible to develop 'second-generation' inhibitors as well as rational drug combinations that can overcome or even prevent acquired resistance to kinase inhibitors, thereby enhancing clinical benefit.