Pathophysiology of EGFR and options of targeting

Abstract

The family of human epidermal growth factor (HER) receptors representing transmembrane receptor kinases consists of the epidermal growth factor receptor (EGFR; HER-1), HER-2, HER-3 and HER-4, respectively. Several soluble ligands of the epidermal growth factor family induce formation of HER receptor homodimers or heterodimers leading to autophosphorylation of tyrosine residues within the cytoplasmatic catalytic kinase domain of the receptor. Interestingly, HER-2 is the preferred recruited heterodimerization partner despite the fact, that it does not bind to any known ligands of the HER family. In the complex with EGFR, HER-2 potentiates EGFR signaling by enhancing the binding affinity of its ligand EGF, reducing its degradation and predisposing the receptor to recycling. HER receptors activate numerous downstream pathways in response to extracellular ligand-binding including cell differentiation, proliferation (MAPK), migration and survival (PI3K). Dysregulation of HER mediated cellular pathways has been implicated in the carcinogenesis of breast cancer. Especially amplification of the HER-2 gene with consecutive overexpression of the HER-2 receptor, found in 25–30% of all breast cancer cases is associated with the aggressive basal cell like tumor type and significantly shortened survival and specific resistances against certain types of cytotoxic and endocrine agents.