Abstract
BackgroundThymidylate 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.ResultsMPM 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 MethodsIn 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.ConclusionsThese data indicate that dasatinib sensitizes mesothelioma cells to PEM through TS down-regulation.
Highlights
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor strongly linked to asbestos exposure [1, 2]
Apoptosis and migration, as well as thymidylate synthase (TS) expression and SRC activation have been assessed. These data indicate that dasatinib sensitizes mesothelioma cells to PEM through TS down-regulation
A phase III study reported an inferior activity in terms of overall survival of the combination of cisplatin and PEM compared to cisplatin and gemcitabine for squamous cell lung carcinoma and opposite data for non-squamous non-small cell lung cancer [7] and this differential efficacy was related to TS mRNA expression, being higher in squamous cell carcinoma of the lung [8, 9]
Summary
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor strongly linked to asbestos exposure [1, 2]. Intrinsic and acquired resistance mechanisms, including high thymidylate synthase (TS) expression, may be responsible for the limited efficacy of PEM in MPM [5] and, in several cell lines, the induction of resistance to PEM was associated with increased levels of TS mRNA expression [6]. A phase III study reported an inferior activity in terms of overall survival of the combination of cisplatin and PEM compared to cisplatin and gemcitabine for squamous cell lung carcinoma and opposite data for non-squamous non-small cell lung cancer [7] and this differential efficacy was related to TS mRNA expression, being higher in squamous cell carcinoma of the lung [8, 9]. 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
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