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Expression and pharmacological inhibition of thymidylate synthase and Src kinase in nonsmall cell lung cancer
Author(s) -
Ceppi Paolo,
Rapa Ida,
Lo Iacono Marco,
Righi Luisella,
Giorcelli Jessica,
Pautasso Marisa,
Billè Andrea,
Ardissone Francesco,
Papotti Mauro,
Scagliotti Giorgio V.
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26188
Subject(s) - thymidylate synthase , lung cancer , cancer research , pemetrexed , proto oncogene tyrosine protein kinase src , tyrosine kinase , biology , cancer , dasatinib , antifolate , cytotoxicity , kinase , chemotherapy , medicine , signal transduction , antimetabolite , in vitro , biochemistry , cisplatin , fluorouracil
Abstract The combination of cytotoxic chemotherapy with signaling pathway inhibitors represents a potential strategy to improve the treatment of nonsmall cell lung cancer (NSCLC). Thymidylate synthase (TS) is an enzyme essential for DNA synthesis, and its overexpression has been associated with the reduced sensitivity to antifolate agents. Src is a tyrosine kinase that modulates the cytotoxicity of cancer cells after drug treatment, and in vitro data indicate that its inhibition could revert the resistance to TS‐inhibiting drugs. Our study investigated the significance of TS and Src expression in NSCLC tissues, and the effects of their pharmacological inhibition in cell lines. In tumor and normal tissues from 94 resected NSCLC patients, TS and Src transcript levels were found positively correlated ( R S = 0.66), associated with patients smoking history and overall survival. At multivariate analysis, TS gene expression was an independent prognostic factor (relative risk (RR) = 1.78, from 1.16 to 2.72; p < 0.01). Immunohistochemical detection in tumor specimens confirmed that Src kinase activation, evaluated by phospho‐specific antibody, was associated to a higher TS expression. In cell lines, dasatinib, a Src‐inhibiting agent, synergistically enhanced pemetrexed‐cytotoxicity of A549 cells, as evaluated by MTT and apoptosis assays. The biological explanation for this interaction was based on the upregulation of TS messenger RNA and protein levels induced by pemetrexed, which was significantly prevented by dasatinib cotreatment. The data of our study suggest that TS and Src may belong to a common pathway that bears prognostic significance in NSCLC, and that Src represents a potential target to improve the efficacy of TS‐inhibiting agents.