Original Paper

siRNA Targeting against EGFR, a Promising Candidate for a Novel Therapeutic Application to Lung Adenocarcinoma
Sumitaka Yamanaka^{a, b}, Zhaodi Gu^a, Masami Sato^{a, b, d}, Rumi Fujisaki^a, Kenichi Inomata^a, Akira Sakurada^b, Akira Inoue^c, Toshihiro Nukiwa^c, Takashi Kondo^b, Akira Horii<sup>a

a</sup>Department of Molecular Pathology, Tohoku University School of Medicine and Departments of
^bThoracic Surgery and
^cRespiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, and
^dDivision of Thoracic Surgery, Miyagi Cancer Center Hospital, Natori, Japan

Address of Corresponding Author

Pathobiology 2008;75:2-8 (DOI: 10.1159/000113789)

  Key Words

• Epidermal growth factor receptor
• Gefitinib
• Lung cancer
• siRNA

  Abstract

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.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Dr. Akira Horii
Department of Molecular Pathology
Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku
Sendai 980-8575 (Japan)
Tel. +81 22 717 8042, Fax +81 22 717 8047, E-Mail horii@mail.tains.tohoku.ac.jp

  Article Information

Received: May 31, 2007
Accepted after revision: August 29, 2007
Published online: March 11, 2008
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 1, Number of References : 24