AUTHOR=Baird Anne-Marie , Easty David , Jarzabek Monika , Shiels Liam , Soltermann Alex , Klebe Sonja , Raeppel Stéphane , MacDonagh Lauren , Wu Chengguang , Griggs Kim , Kirschner Michaela B. , Stanfill Bryan , Nonaka Daisuke , Goparaju Chandra M. , Murer Bruno , Fennell Dean A. , O'Donnell Dearbhaile M. , Barr Martin P. , Mutti Luciano , Reid Glen , Finn Stephen , Cuffe Sinead , Pass Harvey I. , Opitz Isabelle , Byrne Annette T. , O'Byrne Kenneth J. , Gray Steven G. TITLE=When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All? JOURNAL=Frontiers in Endocrinology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00089 DOI=10.3389/fendo.2019.00089 ISSN=1664-2392 ABSTRACT=

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.