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

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

doi:10.3389/fendo.2019.00089

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

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 ReidStephen Finn, Sinead Cuffe, Harvey I. Pass, Isabelle Opitz, Annette T. Byrne, Kenneth J. O’Byrne, Steven G. Gray

College of Medicine and Public Health

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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.

Original language	English
Article number	89
Number of pages	19
Journal	Frontiers in Endocrinology
Volume	10
DOIs	https://doi.org/10.3389/fendo.2019.00089
Publication status	Published - 26 Feb 2019

Bibliographical note

Copyright © 2019 Baird, Easty, Jarzabek, Shiels, Soltermann, Klebe, Raeppel, MacDonagh, Wu, Griggs, Kirschner, Stanfill, Nonaka, Goparaju, Murer, Fennell, O'Donnell, Barr, Mutti, Reid, Finn, Cuffe, Pass, Opitz, Byrne, O'Byrne and Gray. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Keywords

BMS-777607
LCRF-0004
Malignant Pleural Mesothelioma
MET
MST1
RON
RTK
TAM

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Baird, A. M., Easty, D., Jarzabek, M., Shiels, L., Soltermann, A., Klebe, S., Raeppel, S., MacDonagh, L., Wu, C., Griggs, K., Kirschner, M. B., Stanfill, B., Nonaka, D., Goparaju, C. M., Murer, B., Fennell, D. A., O’Donnell, D. M., Barr, M. P., Mutti, L., ... Gray, S. G. (2019). When RON MET TAM in mesothelioma: All druggable for one, and one drug for all? Frontiers in Endocrinology, 10, [89]. https://doi.org/10.3389/fendo.2019.00089

@article{33c1599dd9d84118b10ba54ef1a11e12,

title = "When RON MET TAM in mesothelioma: All druggable for one, and one drug for all?",

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.",

keywords = "BMS-777607, LCRF-0004, Malignant Pleural Mesothelioma, MET, MST1, RON, RTK, TAM",

author = "Baird, {Anne Marie} and David Easty and Monika Jarzabek and Liam Shiels and Alex Soltermann and Sonja Klebe and St{\'e}phane Raeppel and Lauren MacDonagh and Chengguang Wu and Kim Griggs and Kirschner, {Michaela B.} and Bryan Stanfill and Daisuke Nonaka and Goparaju, {Chandra M.} and Bruno Murer and Fennell, {Dean A.} and O{\textquoteright}Donnell, {Dearbhaile M.} and Barr, {Martin P.} and Luciano Mutti and Glen Reid and Stephen Finn and Sinead Cuffe and Pass, {Harvey I.} and Isabelle Opitz and Byrne, {Annette T.} and O{\textquoteright}Byrne, {Kenneth J.} and Gray, {Steven G.}",

note = "Copyright {\textcopyright} 2019 Baird, Easty, Jarzabek, Shiels, Soltermann, Klebe, Raeppel, MacDonagh, Wu, Griggs, Kirschner, Stanfill, Nonaka, Goparaju, Murer, Fennell, O'Donnell, Barr, Mutti, Reid, Finn, Cuffe, Pass, Opitz, Byrne, O'Byrne and Gray. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.",

year = "2019",

month = feb,

day = "26",

doi = "10.3389/fendo.2019.00089",

language = "English",

volume = "10",

journal = "Frontiers in Endocrinology",

issn = "1664-2392",

publisher = "NA",

}

Baird, AM, Easty, D, Jarzabek, M, Shiels, L, Soltermann, A, Klebe, S, Raeppel, S, MacDonagh, L, Wu, C, Griggs, K, Kirschner, MB, Stanfill, B, Nonaka, D, Goparaju, CM, Murer, B, Fennell, DA, O’Donnell, DM, Barr, MP, Mutti, L, Reid, G, Finn, S, Cuffe, S, Pass, HI, Opitz, I, Byrne, AT, O’Byrne, KJ & Gray, SG 2019, 'When RON MET TAM in mesothelioma: All druggable for one, and one drug for all?', Frontiers in Endocrinology, vol. 10, 89. https://doi.org/10.3389/fendo.2019.00089

TY - JOUR

T1 - When RON MET TAM in mesothelioma

T2 - All druggable for one, and one drug for all?

AU - Baird, Anne Marie

AU - Easty, David

AU - Jarzabek, Monika

AU - Shiels, Liam

AU - Soltermann, Alex

AU - Klebe, Sonja

AU - Raeppel, Stéphane

AU - MacDonagh, Lauren

AU - Wu, Chengguang

AU - Griggs, Kim

AU - Kirschner, Michaela B.

AU - Stanfill, Bryan

AU - Nonaka, Daisuke

AU - Goparaju, Chandra M.

AU - Murer, Bruno

AU - Fennell, Dean A.

AU - O’Donnell, Dearbhaile M.

AU - Barr, Martin P.

AU - Mutti, Luciano

AU - Reid, Glen

AU - Finn, Stephen

AU - Cuffe, Sinead

AU - Pass, Harvey I.

AU - Opitz, Isabelle

AU - Byrne, Annette T.

AU - O’Byrne, Kenneth J.

AU - Gray, Steven G.

N1 - Copyright © 2019 Baird, Easty, Jarzabek, Shiels, Soltermann, Klebe, Raeppel, MacDonagh, Wu, Griggs, Kirschner, Stanfill, Nonaka, Goparaju, Murer, Fennell, O'Donnell, Barr, Mutti, Reid, Finn, Cuffe, Pass, Opitz, Byrne, O'Byrne and Gray. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

PY - 2019/2/26

Y1 - 2019/2/26

N2 - 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.

AB - 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.

KW - BMS-777607

KW - LCRF-0004

KW - Malignant Pleural Mesothelioma

KW - MET

KW - MST1

KW - RON

KW - RTK

KW - TAM

UR - http://www.scopus.com/inward/record.url?scp=85068990791&partnerID=8YFLogxK

U2 - 10.3389/fendo.2019.00089

DO - 10.3389/fendo.2019.00089

M3 - Article

AN - SCOPUS:85068990791

SN - 1664-2392

VL - 10

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

M1 - 89

ER -

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

Abstract

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Keywords

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