EGFR/Met association regulates EGFR TKI resistance in breast cancer

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor shown to be mechanistically involved in cell growth and survival (reviewed in [1]). Ligand activation of EGFR results in homo- and hetero-dimerization with other members of the EGFR family of receptor (reviewed in [1]). This dimerization enables EGFR to autophosphorylate, resulting in the recruitment of signaling proteins to the receptor (reviewed in [1]). Approximately 30% of human breast tumors overexpress EGFR, and this overexpression correlates with a loss of estrogen responsiveness and a poor prognosis [2-5]. Despite strong correlative evidence from human breast tumors, transgenic mouse models have clearly demonstrated that overexpression of the EGFR alone is insufficient for tumor formation [6]. EGFR tyrosine kinase inhibitors (TKIs) are in clinical use in lung and pancreatic cancers, but have yet to demonstrate efficacy in breast cancer. We and others have recently identified the receptor tyrosine kinase Met as a key regulator of EGFR tyrosine kinase inhibitor resistance in cancer [7,8].Met also is overexpressed in breast cancer cells and human breast tumors and its expression correlates with EGFR expression in basal type breast cancers [9-11]. Met or hepatocyte growth factor receptor is characterized as a receptor tyrosine kinase [12]. However, unlike EGFR, there are two broad mechanisms of Met activation: ligand-dependent and ligand-independent. In the mammary gland, ligand-dependent activation of Met involves the paracrine production of HGF by stromal cells, including fibroblasts [13]. Ligand-independent activation of Met has been shown to occur through a number of mechanisms, including mutation of Met, constitutive dimerization of Met associated with overexpression, pathway activation via hypoxic conditions, transactivation by other membrane proteins (including EGFR), and loss of negative regulators [14].We have previously shown that the kinase activity of Met, in part, regulates EGFR t