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D. Easty
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-014 - The Small Molecule Inhibitor, LCRF004, Is Effective in Targeting the RON/MST1R Pathway in Malignant Pleural Mesothelioma (ID 1311)
09:30 - 09:30 | Author(s): D. Easty
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. We have previously identified RON as frequently activated in MPM patient samples and cell lines. RON is a member of the MET proto-oncogene family and is bound by macrophage stimulating protein (MSP). High positivity for total RON by IHC was an independent predictor of favourable prognosis. Additionally, elevated expression levels of MSP correlated with better survival. The aim of this study was to further examine the MSP-RON signalling axis in MPM using a RON inhibitor, LCRF004.
Methods:
MPM cell lines and a normal mesothelial cell line were screened for the expression of RON and MSP at the protein (Western) and mRNA (RT-PCR) level. Downstream mediators affected by MSP stimulation and LCRF004 were identified using a proteome profiler array. The effect of LCRF004 and MSP were examined using proliferation (BrdU ELISA), viability (High Content Analysis), migration (xCELLigence), apoptosis and cell cycle (HCA) assays. A xenograft study was also completed.
Results:
Treatment with LCRF004 resulted in a significant decrease in proliferation, viability and migration in vitro and reduced tumour growth in vivo (p<0.05, compared with vehicle control). In addition, LCRF004 significantly increased apoptosis. In terms of cell cycle, drug treatment decreased cells in 2n, whilst increasing cells in the G0/G1 phase. Experiments are on going to further characterise the mechanism of action of LCRF004.
Conclusion:
The in vivo and in vitro data generated in this study, indicates that the MSP-RON signalling axis is a potential target in MPM. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM.
