title: Dual inhibition of EGFR and mTOR pathways in small cell lung cancer.
abstract: 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.
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Schmid
authors.forename: Z
authors.initials: Z
authors.lastname: Bago-Horvath
authors.forename: W
authors.initials: W
authors.lastname: Berger
authors.forename: A
authors.initials: A
authors.lastname: Haitel
authors.forename: D
authors.initials: D
authors.lastname: Cejka
authors.forename: J
authors.initials: J
authors.lastname: Werzowa
authors.forename: M
authors.initials: M
authors.lastname: Filipits
authors.forename: B
authors.initials: B
authors.lastname: Herberger
authors.forename: H
authors.initials: H
authors.lastname: Hayden
authors.forename: W
authors.initials: W
authors.lastname: Sieghart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D000068338:Everolimus; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D029867:Xenopus Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011799:Quinazolines; D029867:Xenopus Proteins; C437083:trhd protein, Xenopus; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus