TRANS RECEPTOR INHIBITION OF HUMAN GLIOBLASTOMA CELLS BY ERBB FAMILY ECTODOMAINS

Our aim has been to understand the features of erbB receptor homo- and heterodimer assembly to develop approaches to disrupt receptor activa tion, We have developed a general approach to cause erbB receptor-spec ific trans inhibition of human neoplasia, The clonal progression of hu man astrocytomas to a more malignant phenotype often involves the ampl ification and overexpression of the epidermal growth factor receptor ( EGFr) gene, We have selectively targeted the EGFr In human glioblastom a cells with kinase-deficient mutants of the erbB family derived from the ectodomain of the Neu oncogene that are able to form heterodimers with EGFr and inhibit EGFr-dependent phenotypes. In EGFr-positive U87M G human glioblastoma cells, expression of the Neu ectodomain inhibits EGF-, but not platelet-derived growth factor-, induced DNA synthesis; inhibits cell proliferation in the presence of EGF, but not platelet-d erived growth factor; inhibits the ability of U87MG to form colonies I n soft agar; and inhibits transforming efficiency in athymic mice. The se studies establish that EGFr-mediated signal transduction is importa nt in the maintenance of malignant glioma, and that trans receptor inh ibition is a novel way to abrogate abnormal growth of these tumors, Ne u ectodomains will be useful in determining the manner in which the EG Fr contributes to glial tumorigenesis and in the design of pharmaceuti cals that disable erbB family oncoproteins. In addition, these studies provide a rationale for the application of the Neu ectodomain in gene therapy approaches to human malignant glioma and, potentially, to oth er systemic epithelial malignancies expressing erbB family receptors.