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.
Schmid
K
K
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Bago-Horvath
Z
Z
Berger
W
W
Haitel
A
A
Cejka
D
D
Werzowa
J
J
Filipits
M
M
Herberger
B
B
Hayden
H
H
Sieghart
W
W
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
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