Mechanisms of resistance to BCR-ABL and other kinase inhibitors

In this article, we are reviewing the molecular mechanisms that lead to kinase inhibitor resistance. As the oncogenic BCR-ABL kinase is the target of the first approved small-molecule kinase inhibitor imatinib, we will first focus on the structural and mechanistic basis for imatinib resistance. We will then show ways how next generations of BCR-ABL inhibitors and alternative targeting strategies have helped to offer effective treatment options for imatinib-resistant patients. Based on these insights, we discuss commonalities and further mechanisms that lead to resistance to other kinase inhibitors in solid tumors. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).

► We describe the mode of action of the BCR-ABL kinase inhibitor imatinib.
► Different mechanisms leading to imatinib resistance are discussed.
► New generations of BCR-ABL inhibitors are presented.
► Resistance mechanisms to other approved kinase inhibitors are described.