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Research Articles: Therapeutics, Targets, and Development

SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells

¹ Molecular Medicine and ² Information Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California and ³ Department of Oncology, Wyeth Research, Pearl River, New York

Requests for reprints: Richard Jove, Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-301-8179; Fax: 626-256-8708. E-mail: rjove{at}coh.org

Abstract

Src family kinase activity is elevated in many human tumors, including breast cancer, and is often associated with aggressive disease. We examined the effects of SKI-606 (bosutinib), a selective Src family kinase inhibitor, on human cancer cells derived from breast cancer patients to assess its potential for breast cancer treatment. Our results show that SKI-606 caused a decrease in cell motility and invasion of breast cancer cell lines with an IC₅₀ of 250 nmol/L, which was also the IC₅₀ for inhibition of cellular Src kinase activity in intact tumor cells. These changes were accompanied by an increase in cell-to-cell adhesion and membrane localization of β-catenin. By contrast, cell proliferation and survival were unaffected by SKI-606 at concentrations sufficient to block cell migration and invasion. Analysis of downstream effectors of Src revealed that SKI-606 inhibits the phosphorylation of focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk-associated substrate (p130^Cas), with an IC₅₀ similar to inhibition of cellular Src kinase. Our findings indicate that SKI-606 inhibits signaling pathways involved in controlling tumor cell motility and invasion, suggesting that SKI-606 is a promising therapeutic for breast cancer. [Mol Cancer Ther 2008;7(5):1185–94]

Grant support: Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowships (A. Vultur) and NIH grants CA55652 and CA82533 (R. Jove).

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.

⁴ Supplemental video time-lapse microscopy data available at http://www.cityofhope.org/Researchers/JoveRichard/video.

Received 4/25/07; revised 8/15/07; accepted 2/14/08.