PREFERENTIAL INHIBITION OF GLIOBLASTOMA CELLS WITH WILD-TYPE EPIDERMAL GROWTH-FACTOR RECEPTORS BY A NOVEL TYROSINE KINASE INHIBITOR ETHYL-2,5-DIHYDROXYCINNAMATE

Epidermal growth factor receptor (EGFR) gene overexpression and mutati ons play an important role in the pathogenesis of a variety of maligna nt human cancers. In this study, we rested the effects of a novel EGFR tyrosine kinase inhibitor, ethyl-2,5-dihydroxycinnamate (EtDHC), agai nst related human glioblastoma cell lines expressing specific forms of EGFR gene mutations. EtDHC more potently inhibited cell growth and DN A synthesis in glioblastoma cells with endogenous or overexpressed wil d-type EGFR compared with those with truncated EGFR, by preferentially inhibiting the tyrosine kinase activity and autophosphorylation of th e wild-type EGFR. Higher concentrations of EtDHC were required to inhi bit cells expressing the truncated EGFR. These findings are the revers e of another highly specific tyrosine kinase inhibitor, tyrphostin AG 1478, which preferentially inhibited glioblastoma cells with truncated EGFR compared with those with wild-type EGFR. The differential suscep tibility of various glioblastoma cells to highly specific tyrosine kin ase inhibitors is significant because human gliomas are composed of he terogeneous cells with subsets of cells expressing specific gene mutat ions. This cellular heterogeneity could be one of the reasons why tumo r cells are resistant to chemotherapy. Thus, EtDHC, especially when in combination with drugs targeting other specific gene mutations (such as tyrphostin AO 1478), holds a significant potential for chemotherapy for human glioblastomas.