ErbB Expression, Activation, and Inhibition With Lapatinib and Tyrphostin (AG825) in Human Vestibular Schwannomas

Abstract

Pharmacologic agents targeted against the ErbB family, or the intracellular pathways that mediate their effects, could slow clinical progression of vestibular schwannoma (VS) in patients where other modalities carry a high risk-to-benefit ratio. Determine the identity of the predominant ErbB dimer partners in VS tumors and assess the effects of targeted inhibition of the ErbB molecules on VS growth and proliferation, as well as apoptosis. Academic tertiary referral center. Coimmunoprecipitation and Western blotting of VS tissue, in vitro BrdU assays of proliferation in the presence of lapatinib and tyrphostin (AG825) using primary VS cultures, and annexin V cell death assays and cell cycle assays using propidium iodide staining were performed on HEI193 cell line derived from an neurofibromatosis type 2-associated VS. Activated ErbB family receptor heterodimers in VS contain predominantly epidermal growth factor receptor (EGFR) and ErbB2. A robust, dose-dependent inhibition of VS growth and proliferation with the dual EGFR/ErbB2 inhibitor, lapatinib, was demonstrated. Lapatinib also inhibited EGF-induced VS proliferation. The selective ErbB2 inhibitor, AG825, inhibited growth to a lesser extent. HEI193 demonstrated apoptosis after lapatinib treatment. Dual EGFR and ErbB2 inhibition with lapatinib or combination therapy may provide therapeutic benefit in VS treatment, but further studies are necessary.