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The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvlll, de2–7 EGFR or ΔGFR) has an in-frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvlll has been reported to be tumorspecific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell-specific expression of EGFRvlll in lung has not been well documented, we examined the expression of EGFRvlll 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 EGFRvlll expression in NSCLC than previously described. Interestingly, the presence of EGFRvlll was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvlll in NSCLC, a newly developed phospho-specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvlll in tumors. This study presents evidence, for the first time, that EGFRvlll expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvlll is implicated in the pathogenesis of NSCLC and thus EGFRvlll is a potential therapeutic target in this challenging disease. (Cancer Sci 2003; 94: 50–56)