Abstract 1719: Significance of thymidylate synthase copy numbers for resistance to pemetrexed in lung cancer

Abstract

Abstract Pemetrexed is a multitargeted antifolate with promising clinical activity in non-squamous lung cancer. It targets the folate-dependent enzymes thymidylate synthase (TS), reduced folate carrier, and folylpolygamma-glutamate synthetas, all of which are involved in the de novo biosynthesis of thymidine and purine nucleotides.The primary mechanism of the action of pemetrexed is inhibition of TS, which results in a decrease in the available thymidine necessary for DNA synthesis. We have previously established pemetrexed -resistant lung cancer cell line, and have shown that overexpression of TS resulted in increased pemetrexed resistance. We have also examined that TS copy numbers by quantitative real-time PCR, were increased in pemetrexed-resistant cells. Therefore we investigated TS copy numbers in lung cancer cell lines and clinical samples to examine whether TS copy numbers are the biomarker for pemetrexed sensitivity. First, we examined the correlation of TS copy numbers and 50% cell survival of pemetrexed for 14 lung adenocarcinoma cell lines, and a meaningful relationship was accepted. In addition, we examined TS copy number in 20 bronchoscopic specimens of non-squamous lung cancers, and found that the correlation was also confirmed between TS copy numbers and clinical response. Our study suggests that TS copy number may be a predictive marker for pemetrexed sensitivity in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1719. doi:1538-7445.AM2012-1719