Strategies to overcome resistance to targeted protein kinase inhibitors in the treatment of cancer

Inhibition of oncogenic protein kinases by small compound inhibitors has proven to be a valuable strategy for the directed and target-specific treatment of an ever-increasing number of cancer types. These include the treatment of chronic myeloid leukemia with the Bcr-Abl inhibitor imatinib and non-small-cell lung cancer with the epidermal growth factor inhibitors erlotinib and gefitinib. Unfortunately, initially successful therapy is often hampered by relatively rapid onset of resistance to the drug and subsequent relapse, particularly in patients with advanced disease. In the majority of cases this is caused by expansion of clones containing mutated forms of the targeted kinases, which confer insensitivity to the drug of the cancer cell. In addition, multiple factors including pharmacokinetic issues such as suboptimal drug delivery further contribute to resistance formation. Loss of target dependence due to the activation of parallel signaling pathways has also been reported as cause for acquired drug insensitivity. Here, we discuss currently applied as well as potential future strategies that can be applied to overcome and avoid resistance to drug therapy.