Strategies to target HER2/neu overexpression for cancer therapy

Amplification or overexpression of the HER2/neu (also known as erbB-2) gene has been noted in various types of human cancers. In addition to malignant transformation, the activation of signaling pathways of HER2/neu enhances various metastasis-associated properties and may render cancer cells resistant to conventional therapies. This, at least partially, contributes to the poor prognosis and lower survival rate of patients. Many studies have demonstrated that repression of HER2/neu overexpression suppresses the malignant phenotypes of cancer cells. Therefore, various novel HER2/neu-blocking agents have been developed, several of which have been tested in clinical trials with satisfactory results, including trastuzumab, a HER2/neu monoclonal antibody that has been approved by the FDA in the treatment of HER2/neu-overexpressing breast cancer patients. In this article, we intend to discuss the biological relevance and significance of HER2/neu overexpression in tumorigenesis, metastasis, and resistance to conventional therapy. We also summarize the currently available strategies and combination therapies targeting HER2/neu-overexpressing cancer cells. Although the optimal treatment for HER2/neu-overexpressing cancer patients remains elusive, the initial success of trastuzumab indicates that HER2/neu is a good target for cancer therapy. Further elucidation of HER2/neu-mediated pathways and downstream molecules is critical to provide alternative therapies, overcome drug resistance, and improve the therapeutic outcome for HER2/neu-overexpressing cancer patients. (C) 2003 Elsevier Science Ltd. All rights reserved.