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Can we circumvent resistance to ErbB2-targeted agents by targeting novel pathways?

The recent development of targeted therapies using monoclonal antibodies has added new dimensions to the rapidly evolving field of breast cancer treatment. In particular, the incorporation of trastuzumab into regimens containing existing chemotherapeutic agents has significantly improved clinical outcomes for patients with breast cancer in the adjuvant and metastatic settings. De novo and acquired resistance to this treatment, however, is widespread. A substantial amount of research has therefore been dedicated to the elucidation of molecular mechanisms that could explain resistance to this otherwise effective therapy. Potential mechanisms for resistance to trastuzumab include steric inhibition imposed by other extracellular factors, molecular changes in the target receptor itself (ErbB2), alterations in the regulation of downstream signaling components, and crosstalk with other pathways that could compensate for attenuated ErbB2 signaling. In addition, preclinical and clinical studies have been performed to identify potential methods for overcoming trastuzumab resistance, including targeting alternate ErbB2 epitopes and the combined inhibition of multiple signaling components and/or pathways (vertical or horizontal inhibition). Studies continue to evaluate the most promising approaches for overcoming mechanisms of resistance to trastuzumab and other ErbB2-targeted therapies. This review will summarize the most recent research designed to address this substantial clinical problem and provide clinicians with relevant background for understanding some of the potential molecular mechanisms for resistance to targeted therapies in the treatment of patients with breast cancer.