cad a22 4500 569303265 20200205045443.0 cr unu---uuuuu 190726s2019 xx s 000 0 eng 10.5167/uzh-171740 doi 10.3389/fendo.2019.00089 doi (ZORA)oai:www.zora.uzh.ch:171740 610 ddc 30863365 pmid When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All? [Elektronische Daten] [Anne-Marie Baird, David Easty, Monika Jarzabek, Liam Shiels, Alex Soltermann, Sonja Klebe, Stéphane Raeppel, Lauren MacDonagh, Chengguang Wu, Kim Griggs, Michaela B Kirschner, Bryan Stanfill, Daisuke Nonaka, Chandra M Goparaju, Bruno Murer, Dean A Fennell, Dearbhaile M O'Donnell, Martin P Barr, Luciano Mutti, Glen Reid, Stephen Finn, Sinead Cuffe, Harvey I Pass, Isabelle Opitz, Annette T Byrne, Kenneth J O'Byrne, Steven G Gray] openAccess eu-repo 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 , however BMS-777607 was far superior to LCRF-0004. The and 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. Institute of Pathology and Molecular Pathology zora Clinic for Thoracic Surgery zora Baird Anne-Marie joint author Easty David joint author Jarzabek Monika joint author Shiels Liam joint author Soltermann Alex joint author Klebe Sonja joint author Raeppel Stéphane joint author MacDonagh Lauren joint author Wu Chengguang joint author Griggs Kim joint author Kirschner Michaela B. joint author Stanfill Bryan joint author Nonaka Daisuke joint author Goparaju Chandra M. joint author Murer Bruno joint author Fennell Dean A. joint author O'Donnell Dearbhaile M. joint author Barr Martin P. joint author Mutti Luciano joint author Reid Glen joint author Finn Stephen joint author Cuffe Sinead joint author Pass Harvey I. joint author Opitz Isabelle joint author Byrne Annette T. joint author O'Byrne Kenneth J. joint author Gray Steven G. joint author Frontiers in Endocrinology 10:89 https://www.zora.uzh.ch/id/eprint/171740/1/Baird_front_Endocrinol_2019.pdf text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora ZORA 856 40 https://www.zora.uzh.ch/id/eprint/171740/1/Baird_front_Endocrinol_2019.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Baird Anne-Marie joint author ZORA 700 1- Easty David joint author ZORA 700 1- Jarzabek Monika joint author ZORA 700 1- Shiels Liam joint author ZORA 700 1- Soltermann Alex joint author ZORA 700 1- Klebe Sonja joint author ZORA 700 1- Raeppel Stéphane joint author ZORA 700 1- MacDonagh Lauren joint author ZORA 700 1- Wu Chengguang joint author ZORA 700 1- Griggs Kim joint author ZORA 700 1- Kirschner Michaela B. joint author ZORA 700 1- Stanfill Bryan joint author ZORA 700 1- Nonaka Daisuke joint author ZORA 700 1- Goparaju Chandra M. joint author ZORA 700 1- Murer Bruno joint author ZORA 700 1- Fennell Dean A. joint author ZORA 700 1- O'Donnell Dearbhaile M. joint author ZORA 700 1- Barr Martin P. joint author ZORA 700 1- Mutti Luciano joint author ZORA 700 1- Reid Glen joint author ZORA 700 1- Finn Stephen joint author ZORA 700 1- Cuffe Sinead joint author ZORA 700 1- Pass Harvey I. joint author ZORA 700 1- Opitz Isabelle joint author ZORA 700 1- Byrne Annette T. joint author ZORA 700 1- O'Byrne Kenneth J. joint author ZORA 700 1- Gray Steven G. joint author ZORA 773 0- Frontiers in Endocrinology 10:89 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article openAccess