Epidermal growth factor receptor family in lung cancer and premalignancy.
Lung cancer, like many other epithelial malignancies, is thought to be the outcome of genetic and epigenetic changes that result in a constellation of phenotypic abnormalities in bronchial epithelium. These include morphologic epithelial dysplasia, angiogenesis, increased proliferative rate, and changes in expression of cell surface proteins, particularly overexpression of epidermal growth factor receptor (EGFR) family proteins. The EFGR family is a group of four structurally similar tyrosine kinases (EGFR, HER2/neu, ErbB-3, and ErbB-4) that dimerize on binding with a number of ligands, including EGF and transforming growth factor alpha. Epidermal growth factor receptor overexpression is pronounced in virtually all squamous carcinomas and is also found in > or = 65% of large cell and adenocarcinomas. It is not expressed in situ by small cell lung carcinoma. Overexpression of EGFR is one of the earliest and most consistent abnormalities in bronchial epithelium of high-risk smokers. It is present at the stage of basal cell hyperplasia and persists through squamous metaplasia, dysplasia, and carcinoma in situ. Recent studies of the effect of inhibitors of receptor tyrosine kinases suggest that patterns of coexpression of multiple members of the EGFR family could be important in determining response. Intermediate endpoints of such trials could include monitoring of phosphorylation levels in signal transduction molecules downstream of the receptor dimers. These trials represent a new targeted approach to lung cancer treatment and chemoprevention that will require greater attention to molecular endpoints than required in past trials.
Franklin
Wilbur A
WA
Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Veve
Robert
R
Hirsch
Fred R
FR
Helfrich
Barbara A
BA
Bunn
Paul A
PA
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects; D015854:Up-Regulation
D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases