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MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects
E Arriola1, I Cañadas, M Arumí-Uría
1Oncology Department, Hospital del Mar-Parc de Salut Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain. earriola@hospitaldelmar.cat
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.
Insights
MET activation drives aggressive small cell lung carcinoma (SCLC) and predicts poor survival. Inhibiting MET with PHA-665752 reversed this aggressive phenotype in MET mutant SCLC cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Small cell lung carcinoma (SCLC) presents a poor prognosis with limited targeted therapy options.
- The MET pathway is frequently activated in various cancers and represents a potential therapeutic target.
Purpose of the Study:
- To investigate the role of MET signaling in SCLC.
- To evaluate MET as a therapeutic target in SCLC.
Main Methods:
- Assessed MET gene status and protein expression in SCLC cell lines.
- Utilized the MET inhibitor PHA-665752 to study pathway inhibition effects.
- Performed immunohistochemistry for MET and phosphorylated MET (p-MET) in human SCLC samples.
Main Results:
- Hepatocyte growth factor (HGF) stimulation induced MET phosphorylation, proliferation, invasiveness, and growth in MET-mutant SCLC cells.
- PHA-665752 inhibited MET phosphorylation and reversed HGF-induced effects.
- MET and p-MET overexpression occurred in 54% and 43% of SCLC tumors, respectively. MET phosphorylation correlated with significantly poorer overall survival (132 days vs. 287 days).
Conclusions:
- MET activation promotes a more aggressive SCLC phenotype, which can be reversed by MET inhibition.
- MET activation is linked to worse prognosis in SCLC patients, indicating its role in the disease's adverse clinical behavior.
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