Resistance to Targeted Therapies: Refining Anticancer Therapy in the Era of Molecular Oncology

The advent of targeted therapy for treatment of human cancers has added significantly to our armamentarium as we strive to prolong patient survival while minimizing toxicity. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy. The articles in this CCR Focus provide insights into molecular mechanisms of resistance to targeted therapy. Recent discoveries of the molecular pathways that mediate intrinsic resistance to targeted therapy have led to the identification of predictive biomarkers that allow for better patient selection for front line treatment. Equally important, the identification of mechanisms of acquired resistance following front line therapy has led to the discovery of novel agents that overcome these resistance mechanisms. Improving the efficacy of targeted therapies in the future will require expanding our understanding of resistance mechanisms, the development of new generations of rationally designed targeted agents, and translating this information to the clinic to select patients for appropriate therapy. (Clin Cancer Res 2009;15(24):7471-8).