Egfr Receptor Tyrosine Kinase

Growth factor targets cell proliferation and differentiation, and it is now clear that tumor cells may overcome normal regulatory inhibition of proliferation by inappropriate activation of protein tyrosine kinases, such as the erbB receptor family. This particular family includes four distinct members: HER1 epidermal growth factor (EGF) receptor (c-erbBl), HER2 (c-erbB2), HER3 (c-erbB3), and HER4 (c-erbB4). These family members share an overall structure of two cysteine-rich regions in the extracellular domain and a cytoplasmic kinase pocket with a carboxy-terminal tail that is responsible for various downstream stimulation of signal transduction pathways. The overexpression of EGFR is found in many lung tumors.39

EGFR is expressed on the cell membrane of a variety of malignant cells.40'41 Under various physiological conditions, EGF exerts its main action of growth stimulation and initiation of DNA by binding to the corresponding high-affinity cell surface receptor, EGFR, which leads to receptor tyrosine kinase activity, triggering a complex cascade of events that generally leads to cell proliferation. This process is enhanced by anti-apoptotic effects.4243 Both EGFR and c-erbB 2 are the members of the type I family of tyrosine kinase cell surface receptors, and activation of EGFR promotes cell proliferation or differentiation.44 Upon binding with the ligand, the EGFR homodimerizes with the other member of the family.45 Receptor dimerization leads to activation of the EGFR and, subsequently, to cross-phosphorylation of tyrosine residues in the cytoplasmic tail of the receptor. Phosphotyrosine residues in the carboxy-terminus of the receptor serve as high-affinity sites for proteins that, in turn, transmit the growth factor signal inside the cell.46 Overexpression of the EGFR and also c-erbB2 has been found in various cancers such as bladder cancer,47 colon carcinoma,48 and lung cancer.49

In NSCLC the expression profile of EGFR was correlated with a very poor prognosis and also correlated with stage of disease. One study has documented median survival for 121 patients with squamous cell lung cancer, and patients with expression of EGFR had a shorter survival.50

Activation of EGFR was found to activate the phosphorylation of its C-terminus. Several SH2 domains (Src homology) containing proteins have been found to bind to the phosphotyrosine residues of the receptor. Several of these proteins activate different pathways that result in cell proliferation, differentiation, motility, and adhesion.51

EGFR expression was observed in >20% of cells in 11 of 16 (69%) epithelial malignant pleural mesothelioma (MPM) specimens by immunohistochemical analysis. MPM is a locally advancing disease with significant extension and growth into adjacent vital structures, such as esophagus, myocardium, and chest wall. MPM is found to be a very rare kind of aggressive malignancy and there is almost no therapeutic modality.

Squamous cell carcinomas overexpress EGFR very strongly (85%), whereas adenocarcinomas and large-cell carcinomas are positive in approximately 65% cases.52 Some studies suggested that EGFR expression might be correlated with a decreased survival rate.5354 A few studies on lung cancer cell lines have demonstrated that, in NSCLC, a large portion of the examined cell lines expressed the EGF receptor, whereas

SCLC frequently expressed the receptor.55-57 The EGF receptor consists of an external ligand binding site and an internal tyrosine kinase complex.58 The difference between SCLC and NSCLC could be accounted for if SCLC carried the truncated receptor. However, it was found that the monoclonal antibodies EGF-RF4 and EGF-RD10 recognize the internal domain of the EGF receptor.59 The studies with these two antibodies have demonstrated that neither SCLC nor NSCLC carried the truncated receptor. Damstrup et al.49 demonstrated that a relatively high proportion of SCLC cell lines carried high-affinity EGF receptors and expressed EGF receptor mRNA. This group also documented that in the SCLC cell lines, eGf receptors could not be expressed when the protein concentration was found to be lower than 75^g/ml. It was also documented by this group that the binding capacity was stable in the range of 150 to 600^g proteins.

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