Epidermal growth factor receptor mutations in non-small cell lung cancer influence downstream Akt, MAPK and Stat3 signaling.
OBJECTIVE
The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) has been linked to activating mutations in the EGFR gene. So far these mutations have been extensively characterized in established cell lines. The aim of this study was to determine the effects of EGFR mutations on downstream signaling in human tumor specimens.


METHODS
We have looked for mutations of the EGFR gene in specimens of 67 patients with NSCLC and correlated these with EGFR phosphorylation and the activity of its three main downstream signaling cascades Akt, MAPK and Stat3 by immunohistochemistry.


RESULTS
We show that the phosphorylation of tyrosine residues 922 and 1173, but not 1068, are primarily affected by the activating EGFR mutations. Akt activity was significantly higher in patients with EGFR mutations but we found no difference in Stat3 or MAPK phosphorylation. Our results suggest that EGFR mutations not only increase receptor activity, but also alter responses of downstream signaling cascades in human NSCLCs and that these finding differ from results obtained in cell lines.
Zimmer
Sebastian
S
Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany.
Kahl
Philip
P
Buhl
Theresa M
TM
Steiner
Susanne
S
Wardelmann
Eva
E
Merkelbach-Bruse
Sabine
S
Buettner
Reinhard
R
Heukamp
Lukas C
LC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics
D004273:DNA, Neoplasm; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases