Anti-tumor Effects of Erlotinib via Thymidylate Synthase Down-regulation in Pancreatic Cancer Cells

Background/Aim: In pancreatic cancer, gemcitabine and EGFR tyrosine kinase inhibitors (EGFR-TKIs) are common chemotherapy options. Reports have shown that EGFR-TKIs suppress the expression of thymidine synthase (TS), an important enzyme for DNA biosynthesis, and increase sensitivity to gemcitabine in lung cancer. However, no such reports have been made in pancreatic cancer. Materials and Methods: Human pancreatic cancer cell lines MiaPaCa2, Panc1, and BxPc3 were used. TS mRNA and protein expression levels in the cells were analyzed after erlotinib treatment. In addition, the anti-tumor effect of TS knockdown was verified using TS siRNA, along with its synergistic effect when combined with gemcitabine. Results: TS expression was high in MiaPaCa2 and Panc1 cells and low in BxPc3 cells. After erlotinib treatment, TS mRNA and protein levels decreased markedly in MiaPaCa2 cells dose-dependently, but not in Panc1 cells. TS siRNA caused specific downregulation of TS in MiaPaCa2 and Panc1 cells. TS downregulation resulted in an anti-tumor effect in these cells (MiaPaCa2 42%; Panc1 38%; p<0.05), showing a synergistic effect when combined with gemcitabine. Conclusion: Erlotinib could have a synergistic anti-tumor effect when combined with gemcitabine via down-regulation of TS expression.