LUNG CANCER

Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed

Pietro Bertino¹, Camillo Porta², Dario Barbone¹, Serena Germano¹, Sara Busacca¹, Sabrina Pinato¹, Giancarlo Tassi³, Roberto Favoni⁴, Giovanni Gaudino¹, Luciano Mutti⁵

¹ DISCAFF Department and DFB Center, University of Piemonte Orientale "A Avogadro", Novara, Italy
² Medical Oncology, IRCCS San Matteo University Hospital, Pavia, Italy
³ Chest Medicine Unit, Brescia Hospital, Brescia, Italy
⁴ National Cancer Institute, Genoa, Italy
⁵ Local Health Unit, 11 Piemonte, Italy

Correspondence to:
Dr Giovanni Gaudino
DISCAFF Department and DFBC Center, University of Piemonte Orientale"A Avogadro", 28100 Novara, Italy; giovanni.gaudino{at}unipmn.it

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 ß (PDGFRß). PDGFRß 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 PDGFRß 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.

Abbreviations: 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; PDGFRß, PDGF receptor ß; VEGF, vascular endothelial growth factor

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