Combined anti-EGF receptor and anti-HER2 receptor therapy in breast cancer: a promising strategy ready for clinical testing

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Abstract
Human breast carcinomas frequently co-express the epidermal growth factor (EGF) receptor and the other three members of the EGF receptor family (HER2, -3 and -4). These receptors are composed of an extracellular binding domain, a transmembrane lipophilic segment, and an intracellular protein tyrosine kinase domain with a regulatory carboxyl terminal segment. Upon ligand binding, these receptors form homo/heterodimers and activate downstream signaling pathways involved in cell proliferation and survival such as the Ras/Raf/MAPK and the PI3-K/Akt pathways, (for review see Yarden and Sliwkowski 2001 [1]). There is strong evidence that at least two of these receptors, the EGF receptor and HER2, play a role in breast cancer as they are frequently overexpressed and their overexpression confers a more aggressive clinical behavior [2–4]. Furthermore, emerging anti-HER2 and anti-EGF receptor therapies are showing promising activity in the clinical setting. Trastuzumab (Herceptin®), a humanized monoclonal antibody directed at the HER2 has shown activity in HER2 overexpressing metastatic breast carcinomas [5–7], and enhances survival when given in combination with chemotherapy [8]. Similarly, early studies with anti-EGF receptor monoclonal antibodies (MAbs) and small molecule inhibitors of the EGF receptor tyrosine kinase (EGF receptor TKIs) have shown clinical activity in a variety of EGF receptor expressing epithelial tumors [9].