Epidermal growth factor receptor expression, signal pathway, and inhibitors in non-small cell lung cancer

The majority of non-small cell lung cancers (NSCLCs) overexpress the epidermal growth factor receptor (EGFR). The EGFR is frequently overexpressed in preneoplastic bronchial lesions. Thus, EGFR is an excellent potential target for prevention and therapy. New agents developed to inhibit EGFR function include monoclonal antibodies to EGFR and small-molecule receptor tyrosine kinase inhibitors. Preclinical studies showed that both types of inhibitors blocked the in vitro growth of human NSCLC cell lines by inhibiting receptor phosphorylation and phosphorylation of downstream proteins including MAP kinases and AKT. Both types of inhibitors also slowed the growth of human NSCLC tumors in nude mice. Additive or synergistic growth inhibition resulted from the combination of either type of inhibitor with chemotherapy and/or radiotherapy. Clinical phase I and phase II trials showed that both types of inhibitors could be delivered safely, and serum concentrations equivalent to or higher than those required for in vitro activity were achieved. Skin rash was the dose-limiting toxicity with all inhibitors. The skin rash was dose related and reversible. Objective responses were observed in advanced-stage patients refractory to chemotherapy, though the responses were partial responses. Response rates appear higher when the inhibitors are combined with chemotherapy. The results of randomized trials comparing the use of chemotherapy alone with chemotherapy plus the inhibitors are eagerly awaited.