Dasatinib modulates sensitivity to pemetrexed in malignant pleural mesothelioma cell lines

// Valentina Monica 1 , Marco Lo Iacono 1 , Enrico Bracco 1 , Simone Busso 1 , Laura Di Blasio 2 , Luca Primo 2 , Barbara Peracino 3 , Mauro Papotti 1 , Giorgio Scagliotti 1 1 Department of Oncology, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy 2 Department of Oncology, University of Torino, IRCCS Candiolo, Torino, Italy 3 Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Orbassano, Torino, Italy Correspondence to: Valentina Monica, email: valentina.monica@unito.it 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.