Epidermal growth factor receptor gene expression in response to the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in the A549 human lung adenocarcinoma cell line using DNA transfection.
Inhibition of tyrosine kinase activity decreases expression of surfactant protein A in a human lung adenocarcinoma cell line independent of epidermal growth factor receptor.
On sections from both a human lung adenocarcinoma and a squamous cell carcinoma tissue microarray, fluorescence intensity for two epidermal growth factor receptors (EGFR and c-erbB2) correlates with diagnostic pathologic assessment, indicating that immunohistochemistry quantitation can be achieved.
EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines.
The tight association with adenocarcinoma and the high frequency of mutations raise the possibility that EGFR mutations play an important role in the tumorigenesis of adenocarcinoma of lung, especially in East Asians.
The presence of EGFR mutations is a major determinant of gefitinib response, and EGFR tyrosine kinase inhibitors should be tested in clinical trials of first-line treatment of lung adenocarcinomas harboring EGFR mutations.
To further investigate the prevalence of EGFR mutations in relation to ethnic and geographic factors, we evaluated EGFR mutations in a series of Taiwanese patients with primary lung adenocarcinomas who had never been treated with gefitinib.
We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients.
The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.
Thus, analysis of EGFR tyrosine kinase mutations in lung adenocarcinoma is of clinical significance, as it can permit the customization of treatment with EGFR tyrosine kinase inhibitors.
EGFR and HER2 gene amplification may be a late event and EGFR and HER2 protein expression may be associated with the development of adenocarcinoma of the lung.
Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target.
We conclude that mutations of the EGFR kinase domain and the cysteine-rich extracellular domains are infrequent in most types of human cancer apart from lung adenocarcinoma.
Exons 19 and 21 of EGFR, the sites of hotspot mutations in lung adenocarcinomas, were screened in the 11 EGFR-amplified tumors but no mutations were found.