title: MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines.
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.
authors.affiliation: Oncology Department, Hospital del Mar-Parc de Salut Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain. earriola@hospitaldelmar.cat
authors.forename: E
authors.initials: E
authors.lastname: Arriola
authors.forename: I
authors.initials: I
authors.lastname: Cañadas
authors.forename: M
authors.initials: M
authors.lastname: Arumí-Uría
authors.forename: M
authors.initials: M
authors.lastname: Dómine
authors.forename: J A
authors.initials: JA
authors.lastname: Lopez-Vilariño
authors.forename: O
authors.initials: O
authors.lastname: Arpí
authors.forename: M
authors.initials: M
authors.lastname: Salido
authors.forename: S
authors.initials: S
authors.lastname: Menéndez
authors.forename: E
authors.initials: E
authors.lastname: Grande
authors.forename: F R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: S
authors.initials: S
authors.lastname: Serrano
authors.forename: B
authors.initials: B
authors.lastname: Bellosillo
authors.forename: F
authors.initials: F
authors.lastname: Rojo
authors.forename: A
authors.initials: A
authors.lastname: Rovira
authors.forename: J
authors.initials: J
authors.lastname: Albanell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018288:Carcinoma, Small Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D016019:Survival Analysis
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D007211:Indoles; D013450:Sulfones; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met