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¹ Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and ² Department of Surgery and ³ Research Center for Innovative Cancer Therapy of the 21^st Century COE Program for Medical Science, Kurume University, Fukuoka, Japan

Requests for Reprints: Mayumi Ono, Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6098; Fax: 81-92-642-6203. E-mail: mayumi{at}biochem1.med.kyushu-u.ac.jp

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30–50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15–60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.

Key Words: ERK1/2 • Akt • EGF receptor • NSCLC • gefitinib (Iressa, ZD1839)

Grant support: Grant-in-aid for cancer research from Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labor and Welfare, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Iressa is a trademark of the AstraZeneca group of companies.

Received 8/29/03; revised 1/24/04; accepted 1/28/04.