Malignant pleural mesothelioma is an aggressive and highly lethal disease. Conventional chemotherapies and radiation therapy have limited efficacy. Many evidences suggest the roles of receptors tyrosine kinase (RTKs) in mesothelioma pathogenesis, in particular epidermal growth factor (EGFR), Met and Axl. Axl activation is involved in proliferation and inhibition of apoptosis, and its over-expression represents a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents.
Different histological types, epithelioid, sarcomatoid and mixed, of human mesothelioma cell lines were used. Protein levels of Met, Axl and its ligand, growth arrest-specific 6 (Gas6) were evaluated by Western Blot analysis. We conducted in vitro treatments with different doses of Foretinib, dual inhibitor of Met and Axl, in order to demonstrated the variation of cell proliferation and migration through MTT and Colony Forming Assay at the range dose 0.5-1 µM of Foretinib. Lastly, the rate of cell apoptosis was quantified by flow cytometry.
The presence of Met, Axl and Gas6 proteins were found in all cell lines analyzed with different expression pattern. The dose escalation of Foretinib from 0.01 µM to 2 µM strongly inhibited cell proliferation and migration of mesothelioma cell lines. Treatment with Foretinib (at the dose 0.5 µM and 1 µM), determining a significantly increase of apoptosis rate (up to 50%) in specific histological type suggesting a different cell sensibility.
The co-activation of MET and AXL in mesothelioma cell lines suggests that these kinases could serve as novel therapeutic targets. MET and AXL inhibitors could be used as novel anticancer therapies influence clinically meaningful end points including metastatic recurrence and survival in the majority of tumour types.
Clinical trial identification
Legal entity responsible for the study
University of Campania “Luigi Vanvitelli”
Associazione Italiana per la Ricerca sul Cancro (AIRC)
All authors have declared no conflicts of interest.