Journal
BRITISH JOURNAL OF CANCER
Volume 105, Issue 6, Pages 814-823Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2011.298
Keywords
small cell lung cancer; HGF; MET; H69; PHA-665752; mutation
Categories
Funding
- Pla Director d'Oncologia de Catalunya (XBTC)
- Instituto de Salud Carlos III FEDER [RD09/0076/00036, RD09/0076/00101]
- Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I+D+I)
- Instituto de Salud Carlos III (ISCIII)/FEDER [RD06/0020/0109, RD07/0020/2007, PN de I+D+I 2008-20011]
- ISCIII/FEDER - Subdireccion General de Evaluacion y Fomento de la Investigacion [PS09/01594, PS09/01285, PS09/01296]
- DIUE de la Generalitat de Catalunya [2009 SGR 321]
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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. British Journal of Cancer (2011) 105, 814-823. doi: 10.1038/bjc.2011.298 www.bjcancer.com Published online 16 August 2011 (C) 2011 Cancer Research UK
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