This Article Full Text Full Text (PDF) Supplementary Data Correction (v69,p381) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yano, S. Articles by Sone, S. Search for Related Content PubMed PubMed Citation Articles by Yano, S. Articles by Sone, S.

Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Divisions of ¹ Medical Oncology and ² Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan; Departments of ³ Respiratory Medicine and Rheumatology and ⁴ Molecular and Environmental Pathology, University of Tokushima Graduate School, Tokushima, Tokushima, Japan; Departments of ⁵ Thoracic Surgery and ⁶ Pathology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; and ⁷ Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Requests for reprints: Seiji Yano, Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan. Phone: 81-76-265-2780; Fax: 81-76-234-4524; E-mail: syano{at}staff.kanazawa-u.ac.jp.

Key Words: HGF • gefitinib resistance • MET • ErbB3 • Lung cancer

Lung cancer with epidermal growth factor receptor (EGFR)–activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib. [Cancer Res 2008;68(22):9479–87]

This article has been cited by other articles:

				W. Wang, Q. Li, T. Yamada, K. Matsumoto, I. Matsumoto, M. Oda, G. Watanabe, Y. Kayano, Y. Nishioka, S. Sone, et al. Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Clin. Cancer Res., November 1, 2009; 15(21): 6630 - 6638. [Abstract] [Full Text] [PDF]

				K. Sakai, T. Nakamura, K. Matsumoto, and T. Nakamura Angioinhibitory Action of NK4 Involves Impaired Extracellular Assembly of Fibronectin Mediated by Perlecan-NK4 Association J. Biol. Chem., August 14, 2009; 284(33): 22491 - 22499. [Abstract] [Full Text] [PDF]

				Correction: Article on HGF Induces Gefitinib Resistance Cancer Res., January 1, 2009; 69(1): 381 - 381. [Full Text] [PDF]