162P - Targeting the RON/MET/TAM signalling network in mesothelioma

Date 07 May 2017
Event ELCC 2017
Session Poster Display Session
Topics Mesothelioma
Thoracic malignancies
Presenter Anne-Marie Baird
Citation Annals of Oncology (2017) 28 (suppl_2): ii56-ii58. 10.1093/annonc/mdx093
Authors A. Baird1, M. Jarzabek2, L. Shiels2, S. Raeppel3, S. Finn4, S. Cuffe5, H.I. Pass6, I. Schmitt-Opitz7, A.T. Byrne2, S.G. Gray8
  • 1Thoracic Oncology Research Group, St James's Hospital, Dublin 8 - Dublin/IE
  • 2Physiology And Medical Physics & Centre For Systems Medicine, Royal College of Surgeons in Ireland, Dublin/IE
  • 3ChemRF Laboratories, Montreal/CA
  • 4Histopathology And Morbid Anatomy, Trinity College Dublin, Dublin/IE
  • 5Hope Directorate, St James's Hospital, Dublin/IE
  • 6NYU Langone Medical Center, New York/US
  • 7Thoracic Surgery, University Hospital Zürich, Zürich/CH
  • 8Thoracic Oncology Research Group, St James's Hospital, Dublin/IE

Abstract

Background

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer, with limited treatment options and poor survival rates. Simultaneously targeting the RON/MET/TAM family of receptor tyrosine kinases (RTK) may provide an effective novel therapeutic strategy for this disease.

Methods

Expression of RON/MET/TAM and associated ligands were assessed in a cohort of patient samples and MPM cell lines. In vitro and in vivo experiments were undertaken to determine the efficacy of single and multi RTK targeting agents (LCRF0004, RXDX-106, BMS-777607).

Results

mRNA expression of the RON/MET/TAM family was detected in a large panel of normal pleural and MPM cell lines. In a cohort of patient samples, mRNA levels of flRON, sfRON, c-MET, Axl and Tyro3 were increased in MPM tumour samples compared with benign pleural (p < 0.05). There was no difference detected in MERTK expression. In addition, MSP was also elevated in tumour tissue (p < 0.05), whereas GAS6 was not. Furthermore, no MET Exon 14 skipping mutations were detected. All RTK targeting agents displayed in vitro efficacy in terms of reduced proliferation and increased apoptosis. In an in vivo SQ xenograft model the multi-target TKI (BMS-777607) demonstrated superior anti-tumour activity compared with a single targeting agent (LCRF0004).

Conclusions

Data suggests that a multiple TKI, targeting the RON/MET/TAM signalling network, is superior to selective RTKi as an interventional strategy in MPM.

Clinical trial identification

N/A

Legal entity responsible for the study

St. James\'s Hospital

Funding

HRB

Disclosure

All authors have declared no conflicts of interest.