Treatment of vestibular schwannoma cells with ErbB inhibitors

HYPOTHESIS: Aberrant phosphorylation of ErbB family receptor tyrosine kinases (RTK) in human vestibular schwannomas (VSs) renders them susceptible to growth suppression by RTK inhibitors. BACKGROUND: Recent evidence has implicated increased ErbB family receptor tyrosine kinase signaling in VS tumorigenesis; however, the characterization of ErbB receptor activity and the chemotherapeutic potential of RTK inhibitors in VS treatment have not been fully explored. METHODS: To confirm phosphorylation of ErbB receptors in VS, protein extracts from paired VS tumor-vestibular nerve samples were examined using phospho-RTK arrays. ErbB receptor phosphorylation was similarly examined in cultured schwannoma cells, normal Schwann cells, and VS tumor tissues using Western blotting. Also, VS tumor sections were immunostained for members of the ErbB receptor family. The effects of RTK inhibitors on ErbB phosphorylation and cell proliferation were assessed in schwannoma cells after epidermal growth factor receptor (EGFR) inhibitor (Erlotinib) and EGFR/ErbB2 inhibitor (Lapatinib) treatment. RESULTS: VS tumor tissues consistently demonstrated higher levels of phosphorylated ErbB3 compared with paired vestibular nerves. However, cultured VS, malignant schwannoma, and normal Schwann cells demonstrated EGFR phosphorylation. Immunohistochemistry confirmed high expression of ErbB3 in a series of VS tumor sections. Erlotinib inhibited schwannoma cell proliferation with an IC50 value of 2.5 μmol/L, whereas Lapatinib was less potent for growth inhibition. Erlotinib treatment resulted in a decrease of multiple phospho-ErbB receptors in schwannoma cells. CONCLUSION: VS variably express activated ErbB receptors with consistently higher levels of phospho-ErbB3 expression relative to paired vestibular nerve samples. Chemotherapeutic targeting of ErbB3 may be a novel means of inhibiting VS growth.