Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs

Abstract

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, including EGFR, HER2/erbB2, and HER3/erbB3, is an attractive target for antitumor strategies. Aberrant EGFR signaling is correlated with progression of various malignancies, and somatic tyrosine kinase domain mutations in the EGFR gene have been discovered in patients with non^small cell lung cancer responding to EGFR-targeting small molecular agents, such as gefitinib and erlotinib. EGFR overexpression is thought to be the principal mechanism of activation in various malignant tumors. Moreover, an increased EGFR copy number is associated with improved survival in non^small cell lung cancer patients, suggesting that increased expression of mutant and/or wild-type EGFR molecules could be molecular determinants of responses to gefitinib. However, as EGFR mutations and/or gene gains are not observed in all patients who respond partially to treatment, alternative mechanisms might confer sensitivity to EGFR-targeting agents. Preclinical studies showed that sensitivity to EGFR tyrosine kinase inhibitors depends on how closely cell survival and growth signalings are coupled with EGFR, and also with HER2 and HER3, in each cancer. This review also describes a possible association between EGFR phosphorylation and drug sensitivity in cancer cells, as well as discussing the antiangiogenic effect of gefitinib in association with EGFR activation and phosphatidylinositol 3-kinase/Akt activation in vascular endothelial cells.The epidermal growth factor receptor (EGFR) is a member of the erbB family of receptor tyrosine kinase proteins, which also includes HER2/neu (erbB2), HER3 (erbB3), and HER4 (erbB4). These receptors are composed of an extracellular ligand-binding domain, a transmembrane lipophilic domain, and an intracellular tyrosine kinase domain and, with the exception of HER2, all bind to receptor-specific ligands ( Fig. 1A and B). Phosphorylation of the tyrosine kinase domain followed by homodimerization or heterodimerization between different receptors of the same family leads to protein activation (1). Receptor dimerization is promoted by ligand binding, high receptor density from overexpression, and mutations in the kinase domain. Protein activation on the cell surface of cancer cells is believed to promote signaling cascades, cell growth, differentiation, cell survival (apoptosis), drug and radiation sensitivity, cell cycle progression, and angiogenesis (Fig. 1A).For cancer cells, various mechanisms of EGFR activation are now shown: overexpression of ligands and receptors, EGFR gene gain, and activating mutations. Under physiologic conditions, specific soluble ligands bind to the extracellular domains of EGFR, HER3, and HER4, but no ligand has been identified for HER2 (Fig. 1A). Of these ligands, EGF and transforming growth factor-a (TGF-a) selectively bind to EGFR, following dimerization as a homodimer or as a heterodimer with other members, and undergo autophosphorylation at specific tyrosine residues within the intracellula...

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