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

Anne‐Marie Baird ,Luciano Mutti,Annette T Byrne,Alex Soltermann,Martin P Barr,Lauren Macdonagh,Harvey I Pass,Sonja Klebe,Kim Griggs,Daisuke Nonaka,Stephen Finn,Stéphane Raeppel,Michaela B Kirschner,Bruno Murer,Steven G Gray,Bryan Stanfill,Dean A Fennell,Liam Shiels,Glen Reid,Isabelle Opitz,Chandra Goparaju ,Monika A Jarzabek ,David J Easty ,Kenneth J O’byrne ,Dearbhaile M O’donnell ,Chuanhao Wu ,Sinéad Cuffe

doi:10.3389/fendo.2019.00089

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.

Highlights

Malignant Pleural Mesothelioma (MPM) is an aggressive inflammatory cancer, associated with asbestos exposure [1]
Expression data indicated that c-MET (HGFR), MST1R (RON), and members of the TAM receptors, were often activated in MPM (Figure 1A, Supplementary Figure 1A)
We examined the expression of MST1R, C-MET, AXL, and TYRO3 at the mRNA level in a larger panel of MPM cell lines (n = 17)

Summary

Introduction

Malignant Pleural Mesothelioma (MPM) is an aggressive inflammatory cancer, associated with asbestos exposure [1]. The vast majority of patients present at an advanced stage, and as a consequence overall survival is dismal, with most patients dying within 1 year of diagnosis [2, 3]. Conservative estimates suggest that 43,000 people die from this disease each year [4], the actual number is probably much greater [5, 6]. There is an urgent clinical need to identify novel therapeutic avenues in this disease to improve patient outcomes. Several studies have demonstrated that c-MET, Axl, EGFR, ErbB2, ErbB3, IGF1R, and PDGFRβ RTKs are active in MPM [10,11,12,13,14], and that targeting c-MET has anti-proliferative activity in this disease [10]

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Results

Discussion

Conclusion