siRNA Targeting against <i>EGFR,</i> a Promising Candidate for a Novel Therapeutic Application to Lung Adenocarcinoma

Abstract

<i>Objective:</i> 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 <i>EGFR</i> on lung cancer. <i>Methods:</i> We analyzed mutations in <i>EGFR</i>,<i> KRAS</i>,<i> TP53</i>, and <i>ERBB2</i> in 198 surgically resected lung cancer specimens. We then analyzed the effects of gefitinib and siRNA treatment on lung adenocarcinoma cell lines. <i>Results:</i> Mutations in <i>EGFR</i> were found only in adenocarcinoma (35 of 106 adenocarcinoma), mainly in females (73%). Mutually exclusive mutations of <i>EGFR</i> and <i>KRAS</i> genes were observed.Mutations of <i>EGFR</i> were well associated with a positive response to gefitinib. Cells with <i>EGFR</i> mutations were very sensitive to gefitinib as well as siRNA-mediated knockdown of EGFR, those with<i> KRAS</i> mutations responded poorly, and those without mutations of <i>KRAS</i> and <i>EGFR</i> showed moderate responses to both treatments. <i>Conclusions:</i> Our present results imply that (1) mutation analyses of <i>EGFR</i> and <i>KRAS</i> 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 <i>EGFR</i> mutation, probably in those with resistance to gefitinib by acquired mutation in <i>EGFR</i>.