MET in small cell lung carcinoma (SCLC): Effects of a MET inhibitor in SCLC cell lines and prognostic role of MET status in pati

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Author(s): I. Cañadas, M. Arumi, L. Lema, A. Martinez, E. Grande, B. Bellosillo, F. Rojo, A. Rovira, J. Albanell, E. Arriola; IMIM-Hospital del Mar, Barcelona, Spain; Hospital del Mar-IMAS, Barcelona, Spain; Pfizer, Madrid, Spain; Capio-Fundacion Jimenez Diaz, Madrid, Spain
 
Abstract:
Purpose: HGF/MET pathway is aberrantly activated by receptor overexpression and mutations in SCLC preclinical models, enhancing their oncogenicity. The significance of MET expression in SCLC remains unclear. Our aim was to analyze the effects of MET inhibition in chemosensitive/refractory SCLC models and to study the expression pattern and prognostic impact of total and phosphorylated (p) MET in SCLC patients.
Methods: Total and p-MET expression (Western Blot), gene copy number (FISH), and exon 14 activating mutations (sequencing) were evaluated in H69 and H69AR SCLC cell lines. PHA-665752 (PHA), alone or combined with doxorubicin, was used to study the effects of pathway inhibition on viability, colony formation and invasion assays in basal/stimulated conditions (HGF). Fifty-eight SCLC cases were evaluated for MET and p-MET expression by immunohistochemistry. Survival analyses were performed.
 
Results: H69 and H69AR (both R988C mutated) expressed MET at basal conditions, but not p-MET. HGF induced MET phosphorylation, increased proliferation (20%) and protected cells from doxorubicin cytotoxicity. PHA 0.5µM blocked MET phosphorylation, decreased colony formation by 50% in H69, counteracted the cytoprotective effect of HGF and inhibited invasion in H69AR. MET expression was found in 98% normal bronchial epithelia, and 78% tumor samples (overexpression 38%). Activated MET was focally detected in normal and metaplastic mucosa and expressed in 22% tumors. MET expression was associated with improved overall and disease free survival (p: 0.06 and 0.051, respectively). All p-MET positive cases within MET expressing tumors, showed relapsed disease (83% in negative p-MET samples, p=0.065), suggesting MET activation may revert the good prognosis linked to total MET expression.
 
Conclusions: MET activation , results in a more aggressive phenotype in SCLC cells. PHA at MET inhibiting concentrations reverses this phenotype. In SCLC specimens, MET expression was more prevalent than p-MET and associated with raised prognosis. All these data suggest that studies with MET inhibitors should focus on p-MET positive SCLC.