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

Br J Cancer. 2010 Aug 24;103(5):622-8. doi: 10.1038/sj.bjc.6605761. Epub 2010 Aug 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Survival
  • Cells, Cultured
  • ErbB Receptors / antagonists & inhibitors*
  • Erlotinib Hydrochloride
  • Everolimus
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Lung Neoplasms / drug therapy
  • Male
  • Middle Aged
  • 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
  • Xenopus Proteins

Substances

  • Intracellular Signaling Peptides and Proteins
  • Quinazolines
  • Xenopus Proteins
  • trhd protein, Xenopus
  • Everolimus
  • Erlotinib Hydrochloride
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • Sirolimus