%0 Journal Article
%T Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer
%A Rita Nahta
%J ISRN Oncology
%D 2012
%R 10.5402/2012/428062
%X The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways. In this paper, we will discuss proposed mechanisms of trastuzumab resistance, including epitope masking, cross signaling from other cell surface receptors, hyperactive downstream signaling, and failure to induce antibody-dependent cellular cytotoxicity. In addition, we will discuss the molecular mechanisms of action of dual HER2 inhibition, specifically the combination of trastuzumab plus lapatinib or trastuzumab with pertuzumab. We will also discuss data supporting therapeutic combinations of trastuzumab with agents targeted against molecules implicated in trastuzumab resistance. The roles of insulin-like growth factor-I receptor and the estrogen receptor are discussed in the context of resistance to HER2-targeted therapies. Finally, we will examine the major issues that need to be addressed in order to translate these combinations from the bench to the clinic, including the need to establish relevant biomarkers to select for those patients who are most likely to benefit from a particular drug combination. 1. Introduction The HER2 (erbB2/neu) receptor tyrosine kinase gene is amplified and overexpressed at the protein level in 20¨C30% of metastatic breast cancers. HER2 overexpression represents an example of oncogene addiction in many of these cancers, as HER2 blockade or kinase inhibition achieves durable responses in many patients with metastatic HER2-overexpressing breast cancer. The first-line treatment for this subtype of breast cancers is the HER2 monoclonal antibody trastuzumab. In combination with cytotoxic chemotherapy, trastuzumab has revolutionized treatment and clinical outcome for patients whose breast tumors express high levels of the HER2 protein. Despite remarkable success, response rates are usually limited in duration, suggesting that the development of resistance is a clinical problem. Research published during the past decade has identified multiple molecular mechanisms contributing to trastuzumab resistance. In addition, recent studies have suggested novel combinations of drugs that will benefit patients who have shown disease progression on prior
%U http://www.hindawi.com/journals/isrn.oncology/2012/428062/