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.

Loop-Mediated Isothermal Amplification in Core-Shell Beads Assay for the Detection of Tyrosine Kinase AXL Over Expression

“…Met-5A is a human mesothelial cell line immortalized by the transformation of epithelial virus SV40. Met-5A expresses a high level of AXL RNA [31]. To the best of our knowledge, we described for the first time here a LAMP assay for detection of AXL in complex biological samples.…”

Loop-Mediated Isothermal Amplification in a Core-Shell Bead Assay for the Detection of Tyrosine Kinase AXL Overexpression

“…Met-5A is a human mesothelial cell line immortalized by the transformation of epithelial virus SV40. Met-5A expresses a high level of AXL RNA [ 31 ]. To the best of our knowledge, we described for the first time, here, a LAMP assay for the detection of AXL in complex biological samples.…”

A potential signaling axis between RON kinase receptor and hypoxia‐inducible factor‐1 alpha in pancreatic cancer

“…A pharmacological approach using a small molecule RON inhibitor was employed to determine if blocking RON ligand, MSP‐induced RON receptor activation (tyrosine phosphorylation in the kinase domain) inhibits HIF‐1 α expression and invasive behavior of PDAC cells. LCRF, a small molecule RON TKI was recently reported to block MSP/RON signaling and inhibit the growth of malignant pleural mesothelioma 41 . To determine if LCRF is effective in blocking RON phosphorylation and activation in PDAC cells, we initially carried out an LCRF dose–response analysis and determined 400 nM dosage was effective in blocking RON ligand, MSP‐induced phosphorylation of RON tyrosine kinase receptor.…”

“…As RON has been documented to be involved in the development and progression of various tumor types, 13 preclinical/clinical efforts are being aggressively pursued to develop small molecule or antibody‐drug conjugate therapies 15–17 . Recently, a small molecule RON inhibitor, LCRF was reported to block MSP/RON signaling and inhibited the growth of malignant pleural mesothelioma 41 . Notably, we found that this RON TKI was effective in blocking the MSP/RON signaling pathway induced HIF‐1 α expression in the PDAC cells (Figure 3A).…”