Expression of constitutively activated EGFRvIII in non-small cell lung cancer.
The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvIII, de2-7 EGFR or deltaEGFR) has an in-frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvIII has been reported to be tumor-specific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell-specific expression of EGFRvIII in lung has not been well documented, we examined the expression of EGFRvIII in 76 non-small cell lung cancers (NSCLCs) and 10 non-neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor. We found a higher incidence (30 of 76, 39%) of enhanced EGFRvIII expression in NSCLC than previously described. Interestingly, the presence of EGFRvIII was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvIII in NSCLC, a newly developed phospho-specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvIII in tumors. This study presents evidence, for the first time, that EGFRvIII expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvIII is implicated in the pathogenesis of NSCLC and thus EGFRvIII is a potential therapeutic target in this challenging disease.
Okamoto
Isamu
I
Department of Microbiology and Immunology, Kimmel Cancer Institute, Philadelphia, PA 19107, USA.
Kenyon
Lawrence C
LC
Emlet
David R
DR
Mori
Takeshi
T
Sasaki
Ji-ichiro
J
Hirosako
Susumu
S
Ichikawa
Yasuko
Y
Kishi
Hiroto
H
Godwin
Andrew K
AK
Yoshioka
Masakazu
M
Suga
Moritaka
M
Matsumoto
Mitsuhiro
M
Wong
Albert J
AJ
D016475:3T3 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D051381:Rats
D000911:Antibodies, Monoclonal; D009363:Neoplasm Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors