Abstract 5266: Continuous trifluridine treatment in colorectal cancer cell lines- investigating its potential

Abstract

Abstract Background: Trifluridine (FTD) is a key component of the novel, orally-administered, antitumor drug trifluridine/tipiracil, and is approved for treatment of patients with metastatic colorectal and gastric/GEJ cancers refractory to standard chemotherapy. FTD, an antineoplastic thymidine analogue, is incorporated into the genomic DNA of tumor cells, thereby triggering cell death. An international, double-blind, placebo-controlled Phase III study confirmed the efficacy of trifluridine/tipiracil in patients previously treated with standard chemotherapy. However, the clinical benefit of trifluridine/tipiracil in the first-line metastatic setting still remains unknown. Therefore, we analyzed the sensitivity for FTD, 5-FU, L-OHP, and SN-38 in parental and three FTD long-term treated cell lines. Methods: Three human colorectal cancer cell lines (DLD-1, HCT-116, and RKO) and their respective FTD long-term treated cell lines (treated by step-wise increase in concentrations of FTD starting at 1 µM and ending at 400 µM over a 5 month period) were used. Sensitivity assays using crystal violet staining for FTD, 5-FU, L-OHP, and SN-38 and wound healing assay to assess the migration capacity were performed in these cell lines. Further, mRNA was purified and the resulting microarray was utilized to analyze expression profiles. Results: Continuous FTD long-term treated cell lines were resistant to FTD. In the sensitivity assays, the IC50 values in all three continuously FTD treated cell lines increased by >22-fold for FTD, by <2-fold for 5-FU and L-OHP, and by <9-fold for SN-38 (2 to 8.2-fold in three cell lines) compared to those in parental cell lines. We found that FTD long-treated cells had weaker migration ability than parental cells in all three cell lines. Additionally, HIF1A related glycolytic mRNA was downregulated in FTD long-treated cell lines compared to that in parental cell lines. Conclusions: Although long-term treatment with FTD induced resistance in colorectal cancer cell lines, no cross-resistance to other drugs (5-FU, L-OHP) and partial resistance to SN-38 that are used in standard chemotherapy was observed. Therefore, FTD is expected to be effective even after treatment with standard chemotherapy. Although FTD/TPI is currently used in the later line, it is suggested from this basic study that FTD/TPI may be applicable to take to the front line therapy. Citation Format: Kenta Tsunekuni, Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi, Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki, Hideshi Ishii. Continuous trifluridine treatment in colorectal cancer cell lines- investigating its potential [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5266.