Strategies to Overcome Resistance to Targeted Protein Kinase Inhibitors in the Treatment of Cancer
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REVIEW ARTICLE
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Strategies to Overcome Resistance to Targeted Protein Kinase Inhibitors in the Treatment of Cancer Marcus Buschbeck Cancer Epigenetics Laboratory, Center for Genomic Regulation (CRG), Biomedical Research Parc Barcelona (PRBB), Barcelona, Spain
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 2. What Are the Molecular Mechanisms Leading to Resistance? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3. How Do Mutations Affect Sensitivity to the Drug? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 4. Therapeutic Strategies to Overcome Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4.1 Altering the Mode of Drug Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4.2 Second-Generation Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.3 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 5. How Can We Avoid Resistance Formation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Abstract
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.
1. Introd
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