MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines |
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Authors: | Arriola E Cañadas I Arumí-Uría M Dómine M Lopez-Vilariño J A Arpí O Salido M Menéndez S Grande E Hirsch F R Serrano S Bellosillo B Rojo F Rovira A Albanell J |
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Institution: | Oncology Department, Hospital del Mar-Parc de Salut Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain. earriola@hospitaldelmar.cat |
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Abstract: | Background: Small cell lung carcinoma (SCLC) has poor prognosis and remains orphan from targeted therapy. MET is activated in several tumour types and may be a promising therapeutic target.Methods: To evaluate the role of MET in SCLC, MET gene status and protein expression were evaluated in a panel of SCLC cell lines. The MET inhibitor PHA-665752 was used to study effects of pathway inhibition in basal and hepatocyte growth factor (HGF)-stimulated conditions. Immunohistochemistry for MET and p-MET was performed in human SCLC samples and association with outcome was assessed.Results: In MET mutant SCLC cells, HGF induced MET phosphorylation, increased proliferation, invasiveness and clonogenic growth. PHA-665752 blocked MET phosphorylation and counteracted HGF-induced effects. In clinical samples, total MET and p-MET overexpression were detected in 54% and 43% SCLC tumours (n=77), respectively. MET phosphorylation was associated with poor median overall survival (132 days) vs p-MET negative cases (287 days)(P<0.001). Phospho-MET retained its prognostic value in a multivariate analysis.Conclusions: MET activation resulted in a more aggressive phenotype in MET mutant SCLC cells and its inhibition by PHA-665752 reversed this phenotype. In patients with SCLC, MET activation was associated with worse prognosis, suggesting a role in the adverse clinical behaviour in this disease. |
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Keywords: | small cell lung cancer HGF MET H69 PHA-665752 mutation |
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