Dual Tyrosine Kinase Inhibitor for Focal Adhesion Kinase and Insulin-like Growth Factor-I Receptor Exhibits Anticancer Effect in Esophageal Adenocarcinoma In vitro and In vivo

• Published in: Clinical cancer research 2008-07, Vol.14 (14), p.4631-4639
• Main Authors: Watanabe, Nobuyuki, Takaoka, Munenori, Sakurama, Kazufumi, Tomono, Yasuko, Hatakeyama, Shinji, Ohmori, Osamu, Motoki, Takayuki, Shirakawa, Yasuhiro, Yamatsuji, Tomoki, Haisa, Minoru, Matsuoka, Junji, Beer, David G, Nagatsuka, Hitoshi, Tanaka, Noriaki, Naomoto, Yoshio
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Barrett's esophagus; Blotting, Western; Cell Movement - drug effects; Cells, Cultured; Dual tyrosine kinase inhibitor; Enzyme Inhibitors - pharmacology; Esophageal adenocarcinoma; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - enzymology; FAK; Flow Cytometry; Fluorescent Antibody Technique; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Humans; IGF-IR; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Morpholines - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Signal Transduction - drug effects
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4755

Purpose: Focal adhesion kinase (FAK) regulates integrin and growth factor–mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma. Experimental Design: The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro . Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo . Results: Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser 136 occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226. Conclusions: These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma.