Role of the epidermal growth factor receptor (EGFR) in the development of malignant peripheral nerve sheath tumors (MPNST) in patients with neurofibromatosis type 1 (NF1) and in animal models of NF1

J. E. DeClue Ph.D. a, H. Li Ph.D. a, W.C. Vass a, and N. Ratner Ph.D. b

a Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD 20892, and b University of Cincinnati College of Medicine, Cincinnati, OH 45267

AIM: To investigate the role of the EGFR in tumor development in NF1 patients, and in animal models of NF1. METHODS: We have analyzed RGFR expression by immunoblotting extracts from human NF1 patient tumor cell lines, immunohistochemistry of primary tumors, and biochemical assays of downstream signaling pathways such as MAP kinase and PI3' kinase. We have used cells from mouse embryos with targeted disruption of Nf1, and we have also examined EGFR expression in tumors and tumor cell lines from compound heterozygotes with mutant Nf1 and p53 genes. RESULTS: We found that the EGFR is expressed in 4/4 human NF1 patient and 1/1 human non-NF1 patient tumor cell lines; in 7/7 primary human MPNST tumors; in a rat ethylnitrosourea-induced Schwannoma cell line; in every isolate of mouse in vitro-transformed Schwann cells from Nf1 -/- mice; and in 23/24 tumor cell lines from Nf1:p53 compound heterozygous mice. Furthermore, expression of the EGFR in the human and mouse cell lines was associated with enhanced growth of the cells in the presence of EGF This enhanced growth could be blocked by treatment of the cells with EGFR antagonists, including the monoclonal antibody 225, tyrphostin AG1478, and the OSI 774 inhibitor. CONCLUSIONS: We find that EGFR expression is a virtually universal feature of human MPNST and animal models of NF1. The demonstrated biological activity of the EGFR, and the capacity of EGFR inhibitors to antagonize this effect, suggest that it may be an attractive target in the treatment of NF1-related and non-NF1 MPNST.

KEY WORDS: Schwann Cell, Epidermal Growth Factor, Tyrosine Kinase Inhibitors.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Familial and Hereditary Cancer.