HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer

Abstract

Protein tyrosine kinases are tightly regulated enzymes that play an important role in the control of most fundamental cellular processes, including cell proliferation, differentiation, metabolism, migration, and survival. These signaling proteins are the frequent target of oncogenic mutations or other genetic alterations leading to dysregulated tyrosine kinase activity, cellular transformation, and subsequent tumor progression. Many of the known dominant oncogenes encode aberrant protein tyrosine kinases and are causally associated with a significant fraction of human neoplasms, including breast carcinoma. The epidermal growth factor receptor and HER2/neu are two transmembrane tyrosine kinases that are members of the HER (erbB) signaling network. Aberrant signaling by this network is present in a cohort of breast carcinomas. Structure/function studies of these kinases have led to the identification of molecular approaches aimed at disabling signaling by this transforming network. Trastuzumab, a monoclonal antibody that binds the ectodomain of HER2, was recently shown to induce regression of HER2-overexpressing breast cancers, confirming the role of HER2 in tumor maintenance and progression. A rational therapeutic approach that builds on these results with trastuzumab and expands the targeting of the HER network will be presented.