Abstracts from the 2011 BNOS Conference June 29 – July 1 2011 Homerton College Cambridge

摘要

INTRODUCTION: Tumour suppressor merlin deficiency leads to the development of schwannomas, meningiomas and ependymomas. Using our in vitro model of human schwannoma we have demonstrated that merlin-deficiency leads to increased cell proliferation, cell-matrix adhesion and survival involving ErbB2/3, platelet-derived-growth-factor-receptor-β (PDGFR-β), and Insulin-like growth factor receptor-I (IGF-IR) acting via extracellular-signal-regulated-kinase 1/2 (ERK1/2), AKT and JNK. We have inhibited increased proliferation of schwannoma by AZD6244, sorafenib 2, nilotinib, lapatinib 1 and BEZ-235. Since, schwannoma overexpress multiple receptors/signalling pathways the inhibition of a single target is not sufficient. Therefore, all relevant receptors/signalling pathways must be revealed. AXL subfamily RTKs (AXL, SKY, MER and Ron) are over-expressed in cancers correlating with poor prognosis. Expression profiling and phosphoprotein arrays showed that Axl-family receptors are overexpressed/activated in human schwannoma. METHODS: Western blotting, immunohistochemistry, primary human cell culture, proliferation/adhesion assays. RESULTS: AXL, SKY and their ligand Gas-6 are over-expressed as well as activated in human schwannoma cells and tissues leading to increased proliferation and adhesion. CONCLUSIONS: Axl, SKY and Gas-6 constitute new potential therapeutic targets in merlin- deficient tumours.