Mechanisms of Inhibition of the Epidermal Growth Factor Receptor: Implications for Novel Anti-Cancer Therapies

摘要

The epidermal growth factor receptor (EGFR) is a prototypic receptor tyrosine kinase (RTK) and a member of the ErbB family of receptors. The ErbB receptors and their cognate ligands are frequently overexpressed in human cancers, notably carcinoma of the breast. Unfortunately no known secreted or extracellular ErbB receptor inhibitors have been discovered in mammals. Two natural extracellular inhibitors of the highly homologous Drosophila EGF receptor (dEGFR) have been recently discovered in Drosophila melanogaster. One (Argos) resembles a secreted growth factor, the other (Kekkon) is a transmembrane protein. We have discovered a novel mechanism of EGFR regulation by Argos. Argos inhibits EGFR activation by sequestering activating ligand and preventing the growth factor from binding to and activating the receptor. To get a further structural understanding of this inhibition we have produced crystals of Argos for x-ray crystallographic studies. We are also currently screening crystallization conditions for a complex of Argos bound to an epidermal growth factor (EGF). The structural understanding of this inhibition should help lead to novel strategies to target breast cancer that is ErbB regulated.