Objective: To understand the molecular pathogenesis of lung cancer and to establish a novel therapeutic application, we examined the genetic alterations in lung cancer, and studied the effects of gefitinib and siRNA-mediated knockdown of EGFR on lung cancer. Methods: We analyzed mutations in EGFR, KRAS, TP53, and ERBB2 in 198 surgically resected lung cancer specimens. We then analyzed the effects of gefitinib and siRNA treatment on lung adenocarcinoma cell lines. Results: Mutations in EGFR were found only in adenocarcinoma (35 of 106 adenocarcinoma), mainly in females (73%). Mutually exclusive mutations of EGFR and KRAS genes were observed.Mutations of EGFR were well associated with a positive response to gefitinib. Cells with EGFR mutations were very sensitive to gefitinib as well as siRNA-mediated knockdown of EGFR, those with KRAS mutations responded poorly, and those without mutations of KRAS and EGFR showed moderate responses to both treatments. Conclusions: Our present results imply that (1) mutation analyses of EGFR and KRAS provide valuable information about whether or not to apply treatments targeting against EGFR and the selection of dosage for such treatments, and (2) siRNA-mediated knockdown is effective in lung adenocarcinomas with EGFR mutation, probably in those with resistance to gefitinib by acquired mutation in EGFR.

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