Background: Malignant mesothelioma is a cancer which is refractory to current treatments. Imatinib mesylate is a selective inhibitor of tyrosine kinases such as bcr-abl, c-Kit, c-Fms and platelet derived growth factor receptor β (PDGFRβ). PDGFRβ is often overexpressed in mesothelioma cells and is a therapeutic target for imatinib in some solid tumours. A study was undertaken to assess whether imatinib alone or combined with chemotherapeutic agents may be effective for treating mesothelioma.
Methods: Cultures from mesothelioma MMP, REN and ISTMES2 cell lines were treated with imatinib alone or in combination with a chemotherapeutic agent.
Results: Imatinib induced cytotoxicity and apoptosis selectively on PDGFRβ positive mesothelioma cells via blockade of receptor phosphorylation and interference with the Akt pathway. Of the chemotherapeutic agents tested in combination with imatinib, a synergistic effect was obtained with gemcitabine and pemetrexed.
Conclusions: This study provides a rationale for a novel translational approach to the treatment of mesothelioma which relies on enhancement of tumour chemosensitivity by inhibition of Akt.
- HGF, hepatocyte growth factor
- HMC, human mesothelial cells
- LC50, lethal concentration killing 50% of cells
- M-CSF, macrophage colony stimulating factor
- MMe, malignant mesothelioma
- PDGF, platelet derived growth factor
- PDGFRβ, PDGF receptor β
- VEGF, vascular endothelial growth factor
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Published Online First 22 February 2007
GG and LM contributed equally to the study.
This work was supported by research grants to GG from AIRC (Associazione Italiana per la Ricerca sul Cancro), MARF (Mesothelioma Applied Research Foundation) and the Buzzi Foundation (Casale Monferrato, Italy). This work is part of G.I.Me. (Gruppo Italiano per lo Studio e la Terapia del Mesotelioma) network program.
Competing interests: None declared.