MST1R, a receptor tyrosine kinase expressed in malignant pleural mesothelioma.

Abstract

10583 Background: Receptor tyrosine kinases (RTK) represent novel therapeutic targets for the treatment of malignancy. Using a phospho-RTK array strategy we identified macrophage stimulating 1 receptor (MST1R/RON) as being frequently expressed in malignant pleural mesothelioma (MPM). Methods: We investigated the expression and function of RON in 4 MPM cell lines, 1 transformed mesothelial cell line, and 16 MPM and 5 benign mesothelial surgically resected specimens. Western Blot analysis in fresh frozen samples, immunohistochemistry (IHC) on fixed formalin paraffin embedded (FFPE) specimens, and cellular migration assays in cell lines were performed. Results: Western blot analysis detected RON in the fresh frozen tumour and benign pleural specimens and the 4 MPM cell lines but not in the SV-40 transformed normal mesothelial MET-5A cells. MPM expressed different isoforms of RON compared to benign pleural plaques: both benign pleural plaques and MPM expressed the shortform of RON (sf-RON) whereas the larger RON variants, Δ160 and Δ165, were seen in MPM samples only. The presence of RON message was confirmed by RT-PCR in the MPM cell lines. IHC was performed on a TMA array of FFPE samples resected from 352 patients. 94% showed expression as follows – weak (26%), moderate (37%), strong (31%). The correlation of the IHC scores with clinico-pathological and outcomes variables is ongoing. Using a pre-clinical anti-RON monoclonal antibody, migration assays demonstrate that targeting MST1R/RON prevents cellular migration but not proliferation. Conclusions: Based on the phospho-RTK assays and protein expression studies MST1R/RON is frequently expressed in MPM. The migration inhibition assays suggest that RON may be a novel target for therapy in mesothelioma. Previously, MST1R/RON was shown to mediate epithelial mesenchymal transition (EMT). Therefore RON may play a role in the epithelioid to sarcomatoid spectrum of disease seen with mesothelioma. No significant financial relationships to disclose.