Oncotarget

Research Papers:

Dasatinib modulates sensitivity to pemetrexed in malignant pleural mesothelioma cell lines

Valentina Monica _, Marco Lo Iacono, Enrico Bracco, Simone Busso, Laura Di Blasio, Luca Primo, Barbara Peracino, Mauro Papotti and Giorgio Scagliotti

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Oncotarget. 2016; 7:76577-76589. https://doi.org/10.18632/oncotarget.10428

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Abstract

Valentina Monica1, Marco Lo Iacono1, Enrico Bracco1, Simone Busso1, Laura Di Blasio2, Luca Primo2, Barbara Peracino3, Mauro Papotti1, Giorgio Scagliotti1

1Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy

2Department of Oncology, University of Torino, IRCCS Candiolo, Torino, Italy

3Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy

Correspondence to:

Valentina Monica, email: [email protected]

Keywords: pemetrexed, dasatinib, malignant pleural mesothelioma, cell lines, thymidylate synthase

Received: August 17, 2015     Accepted: June 16, 2016     Published: July 06, 2016

ABSTRACT

Background: Thymidylate synthase (TS), one of the key enzymes for thymidine synthesis, is a target of pemetrexed (PEM), a key agent for the systemic therapy of malignant pleural mesothelioma (MPM) and its overexpression has been correlated to PEM-resistance. In MPM, experimental data report activation of the c-SRC tyrosine kinase suggesting it as a potential target to be further investigated.

Results: MPM cell lines showed different sensitivity, being MSTO the most and REN the least sensitive to PEM. REN cells showed high levels of both TS and SRC: dasatinib inhibited SRC activation and suppressed TS protein expression, starting from 100 nM dose, blocking the PEM-induced up regulation of TS protein levels. Dasatinib treatment impaired cells migration, and both sequential and co-administration with PEM significantly increased apoptosis. Dasatinib pretreatment improved sensitivity to PEM, downregulated TS promoter activity and, in association with PEM, modulated the downstream PI3K-Akt-mTOR signaling.

Cell lines and Methods: In three MPM cell lines (MPP89, REN and MSTO), the effects of c-SRC inhibition, in correlation with TS expression and PEM sensitivity, were evaluated. PEM and dasatinib, a SRC inhibitor, were administered as single agents, in combination or sequentially. Cell viability, apoptosis and migration, as well as TS expression and SRC activation have been assessed.

Conclusions: These data indicate that dasatinib sensitizes mesothelioma cells to PEM through TS down-regulation.


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