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    When RON MET TAM in mesothelioma: all druggable for one, and one drug for all?

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    Authors
    Baird, A
    Easty, D
    Jarzabek, M
    Shiels, L
    Soltermann, A
    Klebe, S
    Raeppel, S
    MacDonagh, L
    Wu, C
    Griggs, K
    Kirschner, M
    Stanfill, B
    Nonaka, Daisuke
    Goparaju, C
    Murer, B
    Fennell, D
    O'Donnell, D
    Barr, M
    Mutti, L
    Reid, G
    Finn, S
    Cuffe, S
    Pass, H
    Opitz, I
    Byrne, A
    O'Byrne, K
    Gray, S
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    Affiliation
    Thoracic Oncology Research Group, Labmed Directorate, St. James's Hospital, Dublin, Ireland
    Issue Date
    2019
    
    Metadata
    Show full item record
    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.
    Citation
    Baird AM, Easty D, Jarzabek M, Shiels L, Soltermann A, Klebe S, et al. When RON MET TAM in mesothelioma: all druggable for one, and one drug for all? Front Endocrinol. 2019;10:89.
    Journal
    Frontiers in Endocrinology
    URI
    http://hdl.handle.net/10541/621778
    DOI
    10.3389/fendo.2019.00089
    PubMed ID
    30863365
    Additional Links
    https://dx.doi.org/10.3389/fendo.2019.00089
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.3389/fendo.2019.00089
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