title: A novel Src kinase inhibitor reduces tumour formation in a skin carcinogenesis model.
abstract: 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 homoeostasis and tumorigenesis. 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 12-O-tetradecanoylphorbol-13-acetate (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 7,12-dimethylbenz(a)anthracene/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 that are hyperproliferative pre-malignant 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 chemopreventative properties in patients with hyperproliferative epidermal disorders.
authors.affiliation: Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Serrels
authors.forename: Alan
authors.initials: A
authors.lastname: Serrels
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mason
authors.forename: Christine
authors.initials: C
authors.lastname: Baldeschi
authors.forename: Gabrielle H
authors.initials: GH
authors.lastname: Ashton
authors.forename: M
authors.initials: M
authors.lastname: Canel
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Mackintosh
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D007642:Keratosis / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy; D011230:Precancerous Conditions / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D052117:Benzodioxoles; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases; D013755:Tetradecanoylphorbol Acetate