Expression of constitutively activated EGFRvlll in non‐small cell lung cancer

Abstract

The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvIII, de2-7 EGFR or ∆ ∆ ∆ ∆EGFR) 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 tumorspecific 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 he epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of several human tumors, including those of the brain, breast, lung and head and neck, and is being actively studied as a target for therapy.1-6) Overexpression of the EGFR in multiple human tumors has been extensively documented, and it has become increasingly apparent that alterations within the EGFR gene may be as important as overexpression for oncogenic effect. 7,8) Several different types of alterations that result in aberrant protein products have been identified. [9][10][11] The most common variant, EGFRvIII (also referred to as ∆EGFR, or de2-7 EGFR), is characterized by an inframe deletion of exons 2-7 of the coding sequence, which has been found to be generated by gene rearrangement or aberrant mRNA splicing. [12][13][14][15] This deletion removes 267 amino acids from the extracellular domain of the normal EGFR, creating a unique epitope at the fusion junction. A number of functional differences between EGFRvIII and EGFR have been characterized. [15][16][17][18] Although EGFRvIII fails to bind EGF, the tyrosine kinase in the intracellular portion is constitutively activated, so that the receptor undergoes tyrosine (Tyr) autophosphorylation. 13,16,19,20) We have previously shown that overexpression of EGFRvIII in NIH3T3 cells causes a highly transformed phenotype as a result of the ligand-independent activation of the receptor kinase.16) Furthermore, we have demonstrated the frequent expression of EGFRvIII in a variety of human tumors with or without EGFR amplification, suggesting that EGFRvIII confers a growth advantage upon tumor cells in vivo. [21][22][23][24][25][26] EGFRvIII has also been shown to be an extremely attractive target for anticancer therapy.15) In a rodent model, vaccination with a peptide corresponding to the alteration present in EGFRvIII could both prevent tumor formation and induce the regression of tumors expressing this receptor.27) More recently, it has been shown that systemic treatment of mice bearing tumors expressing EGFRvIII with monoclonal antibodi...

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

“…Before the recent discovery of the somatic mutations in the EGFR kinase domain (4)(5)(6)(7)(8) in non-small cell lung cancers (NSCLC), deletions of the extracellular domain were considered the most frequent EGFR mutations in the different tumor types (9)(10)(11)(12)(13). These deletions have an activating effect on the receptor, giving cells expressing these truncated receptors a proliferative advantage.…”

“…These deletions have an activating effect on the receptor, giving cells expressing these truncated receptors a proliferative advantage. The most common truncated receptor is the variant III EGFR deletion mutant (EGFRvIII, delta 801EGFR, del2-7 EGFR), containing an inframe deletion of exons 2-7 (801 bp) from the extracellular domain, initially characterized at the genomic level in glioblastoma.Studies using immunohistochemical assays with EGFRvIII mutant-specific antibodies suggest that this mutation is present in multiple other tumor types, including NSCLC (10,11,14). However, because of EGFR's large and complex genomic structure (28 exons spanning Ϸ190 kb) and its large intron 1 (123 kb) where genomic deletions frequently occur, it has been difficult to assess and verify the existence of the EGFRvIII mutations at the genomic level.…”

“…Studies using immunohistochemical assays with EGFRvIII mutant-specific antibodies suggest that this mutation is present in multiple other tumor types, including NSCLC (10,11,14). However, because of EGFR's large and complex genomic structure (28 exons spanning Ϸ190 kb) and its large intron 1 (123 kb) where genomic deletions frequently occur, it has been difficult to assess and verify the existence of the EGFRvIII mutations at the genomic level.…”

Molecular determinants of response to matuzumab in combination with paclitaxel for patients with advanced non-small cell lung cancer

“…Theoretically, conformation (20). The EGFRvIII has been found in association with a minority of cases of glioblastoma multiforme (6,40) or NSCLC (7,41) In the current study, 14 patients were assessable by FISH analysis for genomic deletions involving exons 2 -7 of EGFR. We found no evidence of EGFRvIII deletions in these samples (Table 1, Fig.…”

Early Detection of Lung Cancer: A Call for Novel Biomarkers-Review

“…It is found in 39% of tumors and not in normal tissue and may defi ne an early event in lung carcinogenesis (44).…”