CD95-mediated apoptosis of human glioma cells: Modulation by epidermal growth factor receptor activity

The death ligands CD95L and Apo2L/TRAIL are promising investigational agent s for the treatment of malignant glioma. EGFR is overexpressed in a signifi cant proportion of malignant gliomas in vivo. Here, we report that CD95L-in duced cell death is enhanced by EGFR inhibition using tyrphostine AG1478 in 7 of 12 human malignant glioma cell lines. Conversely, CD95-mediated and A po2L-induced cell death are both inhibited by overexpression of EGFR in LN- 229 cells. CD95L-induced cell death augmented by AG1478 is accompanied by e nhanced processing of caspase 8. LN-229 cells overexpressing the viral casp ase inhibitor, crm-A, are not sensitized to CD95L-induced cell death by AG1 478, indicating that EGFR exerts its antiapoptotic properties through a cas pase 8-dependent pathway. These data define a modulatory effect of EGFR-act ivity on death ligand-induced apoptosis and indicate that EGFR inhibition i s likely to improve the efficacy of death ligand-based cancer therapies. Fu rthermore, it is tempting to speculate that EGFR amplification protects tum or cells from death ligand-mediated host immune responses in vivo and that EGFR's effects on death receptor-mediated apoptosis may explain the anti-tu mor effects of non-cytotoxic, unarmed anti-EGFR family antibodies.