The combination of cytotoxic chemotherapy with signaling pathway inhibitors represents a potential strategy to improve the treatment of non-small 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 following drug treatment, and in vitro data indicate that its inhibition could revert the resistance to TS-inhibiting drugs. The present 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 (Rs =0.66), associated with patients smoking history and overall survival. At multivariate analysis, TS gene expression was an independent prognostic factor (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 up-regulation of TS mRNA and protein levels induced by pemetrexed, which was significantly prevented by dasatinib co-treatment. The data of the present 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. © 2011 Wiley-Liss, Inc.

Copyright © 2011 Wiley-Liss, Inc.

PMID: 21618517 [PubMed - as supplied by publisher] Source: National Library of Medicine.