Abstract 702: RON receptor tyrosine kinase: A potential therapeutic target in malignant pleural mesothelioma

Abstract

Abstract BACKGROUND: Expression of receptor tyrosine kinases (RTK) and their cognate ligands has been described in mesothelioma, leading to the hypothesis that autocrine growth pathways could be therapeutic targets of tyrosine kinase inhibitors (TKIs). METHODS: Phospho-RTK arrays were used to evaluate phosphorylation of 42 RTKs in 4 mesothelioma cell lines and 11 mesothelioma surgical specimens. Western Blot analysis, IHC, cellular migration and invasion assays were performed. RESULTS: Tumours contained 14 phospho-RTKs. RON emerged as a frequently identifed kinase which has not been previously reported in mesothelioma. An extended panel of sixteen mesothelioma tumour and five benign pleural tissue samples were characterised by western blot analysis. The presence of RON message was confirmed by RT-PCR with specific primers in mesothelioma cell lines Western blot analysis detected RON in 16 tumours and 4 cell lines but not in the SV-40 transformed normal mesothelial MET-5A cells. Mesothelioma expressed different isoforms of RON compared to benign pleural plaques: both benign pleural plaques and mesotheliomas expressed the shortform of RON (sf-RON), whereas, the larger RON variants, Δ160 and Δ165, were seen in mesothelioma samples. IHC was subsequently carried out on a large series of FFPE samples (n>400), with clinical followup to determine if RON expression correlates with prognosis or response to therapy. Scratch assays using antibodies directed against RON prevented MPM cell line migration CONCLUSIONS: Mesothelioma contains multiple activated RTKs including RON. Previously, RON was shown to mediate epithelial mesenchymal transition (EMT). This may be significant given the epithelioid to sarcomatoid spectrum of mesothelioma. Expression of Δ160 and Δ165 was previously reported in gastric and colorectal cancers and may be associated with oncogenesis. RON has been identified as a therapeutic target in pancreatic cancer and this may also apply in mesothelioma. Functional studies on targeting RON in mesothelioma are ongoing. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 702.