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

• Published in: British journal of cancer Vol. 103; no. 5; pp. 622 - 628
• Main Authors: SCHMID, K, BAGO-HORVATH, Z, BERGER, W, HAITEL, A, CEJKA, D, WERZOWA, J, FILIPITS, M, HERBERGER, B, HAYDEN, H, SIEGHART, W
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 24.08.2010
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Cell Survival; Cells, Cultured; ErbB Receptors - antagonists & inhibitors; Erlotinib Hydrochloride; Everolimus; Female; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Lung cancer; Lung Neoplasms - drug therapy; Male; Medical sciences; Middle Aged; Pneumology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Quinazolines - administration & dosage; Signal Transduction - drug effects; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - metabolism; TOR Serine-Threonine Kinases; Translational Therapeutics; Tumors; Tumors of the respiratory system and mediastinum; Xenopus Proteins; Antineoplastic agent; Lung disease; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Targeted therapy; Quinazoline derivatives; Transferases; Lung cancer; Bonchopulmonary small cell carcinoma; Enzyme inhibitor; Malignant tumor; Epidermal growth factor receptor; EGFR; Cancerology; Treatment; Erlotinib; Mammalian target of rapamycin; mTOR; Bronchus disease; small cell lung cancer; RAD001; Protein-tyrosine kinase; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605761

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). 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. 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. The combined inhibition of EGFR/mTOR pathways could be a promising approach to treat SCLC.