Preliminary Data Suggestive Of A Novel Translational Approach To Mesothelioma Therapy: Imatinib Mesylate With Gemcitabine Or Pemetrexed

Thorax. Published Online First: 20 February 2007. doi:10.1136/thx.2006.069872 [Link]

Pietro Bertino ¹, Camillo Porta ², Dario Barbone ¹, Serena Germano ¹, Sara Busacca ¹, Sabrina Pinato ¹, Giancarlo Tassi ³, Roberto Favoni ⁴, Giovanni Gaudino ^1* and Luciano Mutti ⁵

¹ DISCAFF Department and DFB Center, University of Piemonte Orientale "A. Avogadro", Novar, Italy
² Medical Oncology, IRCCS San Matteo University Hospital, Pavia, Italy, Italy
³ Chest Medicine Unit, Brescia Hospital, Brescia, Italy, Italy
⁴ National Cancer Institute, Genoa, Italy, Italy
⁵ Local Health Unit 11 Piemonte/Institute for Research and Care "S. Maugeri" Foundation, P, Italy

^* To whom correspondence should be addressed. E-mail: giovanni.gaudino@unipmn.it.

Abstract

Malignant mesothelioma is a cancer refractory to current therapies. Imatinib Mesylate (STI571, Glivec^TM) is a selective inhibitor of tyrosine kinases as bcr-abl, c-Kit, c-Fms and Platelet Derived Growth Factor Receptorβ (PDGFRβ). PDGFRβ is often overexpressed in mesothelioma cells and is a therapeutic target for Imatinib in some solid tumors. The aim of this study is to assess whether Imatinib alone or combined with chemotherapeutic agents may be successful for mesothelioma therapy. Cultures from mesothelioma MMP, REN and ISTMES2 cell lines, were treated with Imatinib alone or in combination with chemotherapeutic. We show here that Imatinib induces cytotoxicity and apoptosis selectively on PDGFRβ positive mesothelioma cells, via blockade of receptor phosphorylation and interference with the Akt pathway. Among chemotherapeutics tested in combination, Imatinib synergizes with Gemcitabine and Pemetrexed. We provide a rationale for a novel translational approach to mesothelioma therapy, relying on enhancement of tumor chemosensitivity, via inhibition of Akt.