Research Articles: Therapeutics, Targets, and Development

Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib

^{1 1}The Beatson Institute for Cancer Research and ²Centre for Oncology and Applied Pharmacology, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, United Kingdom and ³Bristol-Myers Squibb, Princeton, New Jersey

^* To whom correspondence should be addressed. E-mail: v.brunton{at}beatson.gla.ac.uk.

	Abstract

Elevated levels of Src kinase expression have been found in a variety of human epithelial cancers. Most notably in colon cancer, elevated Src expression correlates with malignant potential and is also associated with metastatic disease. Dasatinib (BMS-354825) is a novel, orally active, multi-targeted kinase inhibitor that targets Src family kinases and is currently under clinical evaluation for the treatment of solid tumors. However, the effects of dasatinib on epithelial tumors are not fully understood. We show that concentrations of dasatinib that inhibit Src activity do not inhibit proliferation in 10 of 12 colon cancer cells lines. However, inhibition of integrin-dependent adhesion and migration by dasatinib correlated with inhibition of Src activity, suggesting that dasatinib may have anti-invasive or anti-metastatic activity and antiproliferative activity in epithelial tumors. Using phospho-specific antibodies, we show that inhibition of Src activity in colon cancer cell lines correlates with reduced phosphorylation of focal adhesion kinase and paxillin on specific Src-dependent phosphorylation sites. We have validated the use of phospho-specific antibodies against Src Tyr⁴¹⁹ and paxillin Tyr¹¹⁸ as biomarkers of dasatinib activity in vivo. Colon carcinoma-bearing mice treated with dasatinib showed a decrease in both phospho-Src Tyr⁴¹⁹ and phospho-paxillin Tyr¹¹⁸ in peripheral blood mononuclear cells, which correlated with inhibition of Src activity in the colon tumors. Thus, peripheral blood mononuclear cells may provide a useful surrogate tissue for biomarker studies with dasatinib using inhibition of Src Tyr⁴¹⁹ and paxillin Tyr¹¹⁸ phosphorylation as read-outs of Src activity. [Mol Cancer Ther 2006;5(12):3014-22]

Key Words: Src kinase inhibitor, colon cancer, biomarkers

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