1609P - Role of EGFR and Axl pathways in mediating proliferation and invasiveness of human mesothelioma cell lines

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Basic Science
Mesothelioma
Presenter Morena Fasano
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors M. Fasano, C.M. Della Corte, D. Vitagliano, E. Martinelli, T. Troiani, F. Ciardiello, F. Morgillo
  • Medical Oncology, Second University of Naples, 80131 - Napoli/IT

Abstract

Aim

Preclinical data identified Axl, a tyrosine kinase receptor, as a key mediator of tumor progression and epithelial mesenchymal transition in several types of cancers. It was also demonstrated his role in mediating epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) resistance in lung adenocarcinoma. Recent findings revealed that Axl overexpression in tissue specimes correlated with patients prognosis and survival in malignant pleural mesothelioma (MPM). So, the aim of this work is to investigate EGFR and Axl role in mesothelioma.

Methods

Protein levels and activation status of EGFR and Axl were analyzed in a panel of mesothelioma cell lines (H2452, H2052, H28, MSTO211H). Single agent and combined treatment with foretinib (a multitarget inhibitor of Met, Axl, and others) and gefitinib were tested in vitro to assess synergistic effects on cell proliferation and activation/inhibition of downstream pathways.

Results

By using phospho-receptor tyrosine kinase (RTK) arrays we screened 49 RTKs activation in human mesothelioma cell lines. H2452 and H28 cell lines had both increased level of phosphorylated/activated Axl and EGFR along with increased levels of GAS6 mRNAs levels, indicating an activation of these pathways. Combined treatment with foretinib and gefitinib inhibited cell proliferation, and to a greater extent, migration and invasion capabilities, indicating a potential role of these pathways in the acquisition of mesenchymal phenotype. Response to combined treatment in these cell lines was characterized by inhibition of PI3-K/AKT/mTOR and MAPK signaling.

Conclusions

Our data suggest that both Axl and EGFR pathways may exert a role in proliferation and survival of mesothelioma cells and imply their role as potential new therapeutic targets warranting further clinical evaluation in mesothelioma.

Disclosure

All authors have declared no conflicts of interest.