Abstract
Background8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC).MethodsSFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing.ResultsHigh nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein.ConclusionsOur data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.
Highlights
8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %
Previous work in our laboratory observed that Src family kinase (SFK) are expressed at their highest level in T2 stage carcinomas, suggesting that the SFK pathway is active in clear cell renal cell carcinoma (ccRCC) prior to development of metastasis [12]
The aims of the current study were to evaluate whether SFKs and downstream markers of activation were associated with ccRCC patient prognosis and to investigate the functional effects of two SFK inhibitors, dasatinib and saracatinib, in non-metastatic and metastatic ccRCC cell lines
Summary
8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Roseweir et al BMC Cancer (2016) 16:229 region between SFKs, the Y419 site is not specific to Src, but is associated with activation of all family members [5, 6]. Autophosphorylation of Y419 cannot be assumed to represent only Src kinase activation, instead all SFKs need to be investigated to dissect out which member is being affected in different tumours. There is a need to establish which SFKs are associated with poor prognosis in ccRCC and to determine the mechanisms of action of SFK inhibitors in early (non-metastatic) and late (metastatic) stage tumours
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