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

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...

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Bibliographic Details
Published in:British journal of cancer 2011-09, Vol.105 (6), p.814-823
Main 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
Format: Article
Language:English
Subjects:
631/45/127
692/699/67/1059/602
692/699/67/1612/2143
692/700/1750
Adult
Aged
Aged, 80 and over
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cancer therapies
Carcinoma, Small Cell - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Resistance
Epidemiology
Female
Gene amplification
Growth factors
Hepatocyte Growth Factor - pharmacology
Humans
Indoles - pharmacology
Kinases
Lung cancer
Lung Neoplasms - metabolism
Male
Medical prognosis
Medical research
Medical sciences
Middle Aged
Molecular Diagnostics
Molecular Medicine
Mutation
Neoplasm Invasiveness - prevention & control
Oncology
Phosphorylation
Pneumology
Proto-Oncogene Proteins c-met - antagonists & inhibitors
Proto-Oncogene Proteins c-met - genetics
Proto-Oncogene Proteins c-met - metabolism
Signal Transduction
Sulfones - pharmacology
Survival Analysis
Tumors
Tumors of the respiratory system and mediastinum
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Summary: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
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2011.298