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Curated Journal Articles on Mesothelioma

Dasatinib modulates sensitivity to pemetrexed in malignant pleural mesothelioma cell lines

Oncotarget 2016 July 6 [Epub ahead of print] [Link]

Monica V, Lo Iacono M, Bracco E, Busso S, Di Blasio L, Primo L, Peracino B, Papotti M, Scagliotti G

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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