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

Our plain-English summary of When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?, by A.M. Baird, D. Easty, M. Jarzabek, et al (Frontiers in Endocrinology, 2019).

The study

• Authors: A.M. Baird, D. Easty, M. Jarzabek, L. Shiels, A. Soltermann, S. Klebe, S. Raeppel, L. MacDonagh, C. Wu, K. Griggs, M.B. Kirschner, B. Stanfill, D. Nonaka, C.M. Goparaju, B. Murer, D.A. Fennell, D.M. O'Donnell, M.P. Barr, L. Mutti, G. Reid, S. Finn, S. Cuffe, H.I. Pass, I. Opitz, A.T. Byrne, K.J. O'Byrne, S.G. Gray
• Journal: Frontiers in Endocrinology
• Published: 2019;10:89
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined the receptor MST1R (RON), the related receptors MET, Tyro3 and Axl, and MST1, the protein that binds MST1R, in malignant pleural mesothelioma (MPM). The authors used surgical samples from Leicester, UK (17 MPM, 5 benign), mesothelioma cell lines, tissue arrays from 132 patients, and mice carrying human mesothelioma cells. These genes showed higher levels in tumors than in benign tissue. Patients whose tumors stained highly for MST1R or MST1 survived longer (14 vs. 11 months). In multivariate analysis only MST1 stayed significant. Serum MST1 did not differ between mesothelioma patients and at-risk asbestos-exposed patients (20 per group). In cell lines, LCRF-0004 reduced growth and increased cell death. BMS-777607, which blocks all four receptors, reduced growth of two mesothelioma lines but not a normal line. In mice both drugs slowed tumor growth, and BMS-777607 lengthened median survival. The authors concluded that blocking several receptors at once may work better than blocking MST1R alone. They noted that the mouse work used one cell line and under-the-skin tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining patient tumor samples, mesothelioma cell lines, tissue microarray survival analysis, and mouse xenograft drug experiments
• Who was studied: Fresh-frozen surgical samples from Glenfield Hospital, Leicester, UK: 17 MPM samples (7 epithelioid, 4 sarcomatoid, 6 biphasic) and 5 benign lesions. Also tissue microarrays from 132 MPM patients, mesothelioma and normal mesothelial cell lines, and female nude Balb/c mice injected with NCI-H226 cells.
• Exposure: No asbestos exposure was studied. The treatments tested were drugs: LCRF-0004 (targets MST1R), NRWHE and (IMC)-RON8 (also aimed at MST1R), and BMS-777607 (targets MST1R, c-MET, Axl and Tyro3). Serum MST1 was compared with that of at-risk asbestos-exposed patients.
• Main results:
  • MST1R mRNA was higher in the 17 surgically resected mesotheliomas than in the 5 benign tissues.
  • MST1 mRNA was significantly higher in tumor specimens (n = 17) than in benign samples (n = 5). The text gives p less than 0.0022; the figure legend gives p = 0.0022.
  • In the tissue microarray cohort (n = 132), high MST1R (RON) staining was reported as an independent prognosticator of longer survival: 14 vs. 11 months, log rank p = 0.014.
  • High MST1 staining in the same cohort was also associated with longer survival: 14 vs. 11 months, log rank p = 0.015.
  • On multivariate analysis, only high MST1 expression remained significantly associated with increased survival.
  • Tyro3-positive tumors showed a trend toward longer survival (14.5 vs. 6.6 months) that was not statistically significant (p = 0.052).
  • Serum MST1 was not elevated in mesothelioma patients compared with at-risk (asbestos-exposed) patients (n = 20 per group).
  • No R1018G or R1194H MST1R mutations were found in the cell lines or the 17 surgical samples.
  • NRWHE and (IMC)-RON8 had no significant effect on mesothelioma cell lines and were dropped from further study.
  • In NCI-H226 cells, LCRF-0004 significantly reduced proliferation, and added MST1 did not reverse this.
  • In NCI-H226 cells, LCRF-0004 at 200 nM significantly increased apoptosis (programmed cell death) at 24 and 48 hours.
  • BMS-777607 significantly reduced proliferation of the NCI-H226 and REN mesothelioma cell lines but not of the normal mesothelial cell line LP9.
  • In mice, LCRF-0004 at 20 mg/Kg significantly slowed tumor growth compared with vehicle during week three of treatment (day 61: 517 vs. 821 mm3). Little difference was seen at 10 and 15 mg/Kg.
  • In mice, BMS-777607 increased median survival compared with vehicle (78 days): 101 days at 5 mg/Kg (p = 0.0007), 103 days at 10 mg/Kg (p < 0.0001), and undefined (not reached) at 25 mg/Kg (p < 0.0001).
• The authors' conclusion: The authors concluded that a drug targeting several receptors at once (MST1R/MET/TAM) may be a more effective treatment strategy for MPM than targeting MST1R (RON) alone.
• Limitations the authors state:
  • Only a single MPM cell line was used for the mouse studies.
  • The mouse tumors were grown under the skin of the flank, which does not truly reflect how pleural mesothelioma grows.
  • The authors acknowledged that other cell lines could have been tested to confirm that JU77 and NCI-H226 are not special cases.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Macrophage, Apoptosis, Prognosis.

Related studies

• UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma — E.S. Reardon, V. Shukla, et al. (2021)
• Corrigendum: Why Be One Protein When You Can Affect Many? The Multiple Roles of YB-1 in Lung Cancer and Mesothelioma — T.G. Johnson, K. Schelch, et al. (2019)
• Long non coding RNAs (lncRNAs) are dysregulated in Malignant Pleural Mesothelioma (MPM) — C.M. Wright, M.B. Kirschner, et al. (2013)
• BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma — S. Busacca, M. Sheaff, et al. (2012)
• Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma — V. Volta, E. Ranzato, et al. (2013)
• 3-Dimensional mesothelioma spheroids provide closer to natural pathophysiological tumor microenvironment for drug response studies — H. Shi, E.M. Rath, et al. (2022)

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