Dual inhibition of EGFR and mTOR pathways in small cell lung cancer

BACKGROUND: In this report we investigated the combination of epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) pathway inhibition as a possible new therapeutic strategy for small cell lung cancer (SCLC). METHODS: EGFR, p-AKT, p-ERK, p-mTOR and p-p70s6K protein expressions were studied by immunohistochemistry in 107 small cell lung carcinomas and correlated with clinicopathological parameters. Cells of SCLC were treated with erlotinib +/- RAD001 and analysed for cell viability, proliferation, autophagy, and pathway regulation. RESULTS: Epidermal growth factor receptor, p-AKT, p-ERK, p-mTOR, and p-p70s6K were expressed in 37, 24, 13, 55 and 91% of the tumour specimens of all SCLC patients, respectively, and were not associated with disease-free or overall survival. The expression of EGFR was lower in neoadjuvant-treated patients (P = 0.038); mTOR pathway activation was higher in the early stages of disease (P = 0.048). Coexpression of EGFR/p-mTOR/p-p70s6K was observed in 28% of all patients. EGFR immunoreactivity was associated with p-ERK and p-mTOR expression (P = 0.02 and P = 0.0001); p-mTOR immunoreactivity was associated with p-p70s6K expression (P = 0.001). Tumour cells comprised a functional EGFR, no activating mutations in exons 18-21, and resistance to RAD001 monotherapy. We found synergistic effects of erlotinib and RAD001 combination therapy on the molecular level, cell viability, proliferation and autophagy. CONCLUSIONS: The combined inhibition of EGFR/mTOR pathways could be a promising approach to treat SCLC. British Journal of Cancer (2010) 103, 622-628. doi:10.1038/sj.bjc.6605761 www.bjcancer.com Published online 3 August 2010 (C) 2010 Cancer Research UK