MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines

E. Arriola, I. Cãadas, M. Arumí-Uría, M. Dómine, J. A. Lopez-Vilarĩo, O. Arpí, M. Salido, S. Menéndez, E. Grande, F. R. Hirsch, S. Serrano, B. Bellosillo, F. Rojo, A. Rovira, J. Albanell

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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 (n77), respectively. MET phosphorylation was associated with poor median overall survival (132 days) vs p-MET negative cases (287 days)(P0.001). 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. © 2011 Cancer Research UK All rights reserved.
Original languageEnglish
Pages (from-to)814-823
JournalBritish Journal of Cancer
Volume105
Issue number6
DOIs
Publication statusPublished - 6 Sep 2011

Keywords

  • H69
  • HGF
  • MET
  • mutation
  • PHA-665752
  • small cell lung cancer

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