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

Serrels, A., MacPherson, I.R.J. , Evans, T.R.J. , Lee, F.Y., Clark, E.A., Sansom, O.J. , Ashton, G.H., Frame, M.C. and Brunton, V.G. (2006) Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. Molecular Cancer Therapeutics, 5(12), pp. 3014-3022. (doi: 10.1158/1535-7163.MCT-06-0382)

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 Tyr(419) and paxillin Tyr(118) as biomarkers of dasatinib activity in vivo. Colon carcinoma-bearing mice treated with dasatinib showed a decrease in both phospho-Src Tyr(419) and phospho-paxillin Tyr(118) 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 Tyr(419) and paxillin Tyr(118) phosphorylation as read-outs of Src activity.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Iain and Evans, Professor Jeff and Serrels, Mr Alan and Sansom, Professor Owen
• Authors: Serrels, A., MacPherson, I.R.J., Evans, T.R.J., Lee, F.Y., Clark, E.A., Sansom, O.J., Ashton, G.H., Frame, M.C., and Brunton, V.G.
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Research Group: Centre for Oncology & Applied Pharmacology
• Journal Name: Molecular Cancer Therapeutics
• ISSN: 1535-7163