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When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?.pdf (6.09 MB)

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

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posted on 2019-07-24, 08:31 authored by A-M Baird, D Easty, M Jarzabek, L Shiels, A Soltermann, S Klebe, S Raeppel, L MacDonagh, C Wu, K Griggs, MB Kirschner, B Stanfill, D Nonaka, CM Goparaju, B Murer, DA Fennell, DM O'Donnell, MP Barr, L Mutti, G Reid, S Finn, S Cuffe, HI Pass, I Opitz, AT Byrne, KJ O'Byrne, SG Gray
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.

Funding

The Research in this publication was supported by the following: Health Research Board (HRB) Ireland grants HRA_POR/2010/19 and HRA_POR/2013/237 (SG and A-MB), Buzzi Unicem Foundation for Mesothelioma Research—Grant P24 (SG), NCI/NIH 2U01CA 111295-04 (HP) and a Senior Clinical Research Fellow (SCRF) award Queensland Government, Office of Health, and Medical Research (OHMR) (KO'B).

History

Citation

Frontiers in Endocrinology, 2019, 10:89

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

  • VoR (Version of Record)

Published in

Frontiers in Endocrinology

Publisher

Frontiers Media

issn

1664-2392

Acceptance date

2019-01-31

Copyright date

2019

Available date

2019-07-24

Publisher version

https://www.frontiersin.org/articles/10.3389/fendo.2019.00089/full

Notes

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2019.00089/full#supplementary-material

Language

en

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