Carcinogenesis Advance Access published online on December 5, 2008
Carcinogenesis, doi:10.1093/carcin/bgn278
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A novel Src kinase inhibitor reduces tumour formation in a skin carcinogenesis model
1 Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR
2 The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK
3 Institute of Comparative Medicine, University of Glasgow, Glasgow G61 1QH
4 AstraZeneca, Alderley Park, Macclesfield, UK
5 Current address: ISTEM/CECS/INSERM/UEVE 861, 1 rue de l'internationale, BP 118, 91004 Evry Cedex, France
Correspondence: Dr V Brunton, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, Phone 0131 777 3556; Fax 0131 777 3520, Email v.brunton{at}ed.ac.uk
The Src family tyrosine kinases are key modulators of cancer cell invasion and metastasis and a number of Src kinase inhibitors are currently in clinical development for the treatment of solid tumours. However, there is growing evidence that Src is also upregulated at very early stages of epithelial cancer development. We have investigated the role of Src in mouse skin, which is one of the most tractable models of epithelial homeostasis and tumourigenesis. We found that Src protein expression and activity was regulated during the normal hair cycle, and was increased specifically during the proliferative anagen phase and also in response to the tumour promoter TPA. AZD0530 a selective Src inhibitor prevented the TPA-induced proliferation of basal keratinocytes both in vivo and in vitro. Moreover, treatment with AZD0530 reduced papilloma formation following the well established DMBA/TPA skin carcinogenesis protocol but did not inhibit the subsequent proliferation of the papillomas. Furthermore, AZD0530 did not alter the malignant conversion of papillomas to squamous cell carcinoma suggesting a role for Src in early tumour development in the skin carcinogenesis model, rather than at later stages of tumour progression. Src expression and activity were also seen in human actinic keratoses which are hyperproliferative premalignant skin lesions, indicating that Src may also play a role in the early stages of human skin tumour development. Thus Src inhibitors such as AZD0530 may therefore have chemo-preventative properties in patients with hyperproliferative epidermal disorders.
Tim Green is an employee of AstraZeneca who provided the AZD0530 used in this study
Received July 2, 2008; revised December 3, 2008; accepted December 3, 2008.