DRUG-RESISTANCE OF HUMAN GLIOBLASTOMA CELLS CONFERRED BY A TUMOR-SPECIFIC MUTANT EPIDERMAL GROWTH-FACTOR RECEPTOR THROUGH MODULATION OF BCL-X-L AND CASPASE-3-LIKE PROTEASES

Alterations of the epidermal growth factor receptor (EGFR) gene occur frequently in human malignant gliomas. The most common of these is del etion of exons 2-7, resulting in truncation of the extracellular domai n (Delta EGFR or EGFRvIII), which occurs in a large fraction of nt nov o malignant gliomas (but not in progressive tumors or those lacking p5 3 function) and enhances tumorigenicity, in part by decreasing apoptos is through up-regulation of Bcl-X-L. Here, we demonstrate that the Del ta EGFR concomitantly confers resistance to the chemotherapeutic drug cisplatin (CDDP) by suppression of CDDP-induced apoptosis, Expression of Bcl-X-L was elevated in U87MG.Delta EGFR cells prior to and during CDDP treatment, whereas it decreased considerably in CDDP-treated pare ntal cells. CDDP-induced activation of caspase-3-like proteases was su ppressed significantly in U87MG.Delta EGFR cells. These responses were highly specific to constitutively kinase-active Delta EGFR, because o verexpression of kinase-deficient Delta EGFR (DK) or wild-type EGFR ha d no such affects, Correspondingly, Delta EGFR specific tyrosine kinas e inhibitors reduced Bcl-X-L expression and potentiated CDDP-induced a poptosis in U87MG.Delta EGFR cells. Ectopic overexpression of Bcl-X-L in parental U87MG cells also resulted in suppression of both caspase a ctivation and apoptosis induced by CDDP, These results may have import ant clinical implications for the use of CDDP in the treatment of thos e malignant gliomas expressing Delta EGFR.