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 mutations play an important role in the pathogenesis of a variety of malignant human cancers. In this study, we tested the effects of a novel EGFR tyrosine kinase inhibitor, ethyl-2,5-dihydroxycinnamate (EtDHC), against related human glioblastoma cell lines expressing specific forms of EGFR gene mutations. EtDHC more potently inhibited cell growth and DNA synthesis in glioblastoma cells with endogenous or overexpressed wild-type EGFR compared with those with truncated EGFR, by preferentially inhibiting the tyrosine kinase activity and autophosphorylation of the wild-type EGFR. Higher concentrations of EtDHC were required to inhibit cells expressing the truncated EGFR. These findings are the reverse 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 susceptibility of various glioblastoma cells to highly specific tyrosine kinase inhibitors is significant because human gliomas are composed of heterogeneous cells with subsets of cells expressing specific gene mutations. This cellular heterogeneity could be one of the reasons why tumor cells are resistant to chemotherapy. Thus, EtDHC, especially when in combination with drugs targeting other specific gene mutations (such as tyrphostin AG 1478), holds a significant potential for chemotherapy for human glioblastomas.