Strategies to overcome resistance to targeted protein kinase inhibitors

Key Points The success of kinase inhibitors, such as imatinib and gefitinib, has shown that the development of specific, targeted therapies for cancer is possible. However, there have been many cases of drug resistance to imatinib observed in the clinic and this has consequences for the development of second-generation kinase inhibitors. Current efforts are focused on characterizing the structural determinants of imatinib resistance observed in the clinic. These studies illustrate the importance of features such as the gatekeeper residue, the p-loop and the activation loop of protein kinases. The design of more effective inhibitors based on this structural knowledge, combined with the development of multi-targeted kinase inhibitors that show improved efficacy, hold great promise for cancer therapy. Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR–ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr–Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.