Src family kinase activity is up-regulated in hormone refractory prostate cancer

Tatarov, O., Mitchell, T.J., Seywright, M., Leung, H.Y. , Brunton, V.G. and Edwards, J. (2009) Src family kinase activity is up-regulated in hormone refractory prostate cancer. Clinical Cancer Research, 15(10), pp. 3540-3549. (doi: 10.1158/1078-0432.CCR-08-1857)

Abstract

<b>Purpose</b>: Although Src family kinase (SFK) inhibitors are now in clinical trials for the treatment of androgen-independent prostate cancer (AIPC), there are no studies relating SFK activation to patient survival. This study was designed to determine if SFK activation was up-regulated with the development of AIPC and if patients could be selected who were more likely to respond to therapy. <b>Experimental Design</b>: A unique cohort of matched prostate tumor samples, taken before hormone deprivation therapy and following hormone relapse, was used to determine by immunohistochemistry on an individual patient basis if SFK activity changed with progression to AIPC and whether this related to patient outcome measures. Using matched, hormone-sensitive and hormone-refractory cell lines, we determined if hormone status affected the way prostate cancer cells respond to suppression of SFK activity by the small-molecule inhibitor dasatinib. <b>Results</b>: In the current study, 28% of patients with AIPC exhibited an increase in SFK activity in prostate cancer tissue, these patients had significantly shorter overall survival (<i>P</i><0.0001), and activated SFK expression correlated with the presence of distant metastases. Dasatinib inhibited phosphorylation of Src and Lyn and the downstream substrate FAK in hormone-sensitive and hormone-refractory cell lines. Although migration was reduced by dasatinib in both cell lines, proliferation of hormone-refractory cells only was inhibited. <b>Conclusion</b>: Appropriate patient selection may allow better targeting of prostate cancer patients who are likely to respond to the treatment with SFK inhibitors at the same time improving the outcome of clinical trials.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leung, Professor Hing and Edwards, Professor Joanne
• Authors: Tatarov, O., Mitchell, T.J., Seywright, M., Leung, H.Y., Brunton, V.G., and Edwards, J.
• 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
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432
• ISSN (Online): 1557-3265
• Published Online: 15 May 2009
• Copyright Holders: Copyright © 2009 American Association for Cancer Research
• First Published: First published in Clinical Cancer Research 15(10):3540-3549
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.