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.

Initiation Factor eIF2-independent Mode of c-Src mRNA Translation Occurs via an Internal Ribosome Entry Site

“…The emerging strategies for treatment of breast, lung, prostate, skin, and other cancers are focused on the inhibition of c-Src activities (23,58,60) but not the enhanced supply of c-Src in the tumor cells. Many of the small molecules that target c-Src activities also inhibit other protein kinases and/or show high degrees of cytotoxicity (60).…”

Integrin signalling regulates YAP and TAZ to control skin homeostasis

“…These findings show that integrin-Src signalling is crucial to promote YAP stabilisation and nuclear localisation in basal layer stem/progenitor cells. Accordingly, recent work indicates that skin papillomas induced by DMBA+TPA in mice can be strongly reduced in size and frequency by homozygous deletion of YAP along with one copy of TAZ or by treatment with Dasatinib (Creedon and Brunton, 2012;Serrels et al, 2009;Zanconato et al, 2015). …”

Focal adhesion kinase is required for β-catenin-induced mobilization of epidermal stem cells

“…The expression of FAK is restricted within the skin to the proliferative matrix region of the hair follicles and the outer root sheath or bulge region and is increased in anagen hair follicles induced either during the normal hair cycle or in response to proliferative signals such as TPA or β-catenin activation. Interestingly, the expression of Src is also regulated in a similar manner with increased expression seen in anagen hair follicles (15). However, the direct signals that control FAK and Src expression within the skin are not known.…”

“…In addition, the Src-dependent phosphorylation of FAK leads to the generation of binding sites for a number of other scaffolding proteins and kinases and the FAK/Src complex therefore controls a number of downstream signalling pathways (23,24). Src family kinases are known to play a role in controlling epidermal proliferation (25)(26)(27), and we have shown previously that treatment with the Src kinase inhibitor AZD0530 also reduces chemically induced papilloma formation (15). Therefore, we asked whether the Src/FAK signalling axis could regulate LRC mobilization.…”