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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

Authors' Affiliations: ¹ Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and ² Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University; ³ Shigei Medical Research Institute; ⁴ Okayama Citizens' Hospital, Okayama, Japan; ⁵ Tsukuba Research Institute, Novartis Pharma K.K., Tsukuba, Japan; and ⁶ Department of Surgery, Section of Thoracic Surgery, University of Michigan Medical School, Ann Arbor, Michigan

Requests for reprints: Yoshio Naomoto, Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7257; Fax: 81-86-221-8775; E-mail: ynaomoto{at}md.okayama-u.ac.jp.

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 Ser¹³⁶ 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.