TAS-102, a novel antitumor agent: a review of the mechanism of action

Abstract

Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.

Keywords: 5-Fluorouracil; Fluoropyrimidines; Mechanism of action; Metastatic colorectal cancer; TAS-102; Thymidylate synthase.

Figure 1

Mechanism of action of TAS-102: comparison with 5-FU-based fluoropyrimidines. Figure adapted from Wilson PM et al. Nat Rev Clin Oncol. 2014;11(5):282-298. Permission pending. 5′dFCR: 5′-deoxy-5-fluorocytidine; 5′dFUR: 5′-deoxy-5-fluorouridine; 5-FU: 5-fluorouracil; CDHP: 5-chloro-2,4-dihydroxypyridine; DPD: dihydropyrimidine dehydrogenase; dTTP: thymidine triphosphate; F₃dTMP: trifluoromethyl deoxyuridine 5′-monophosphate; F₃dTTP: trifluoromethyl deoxyuridine 5′-triphosphate; FdUDP: fluorodeoxyuridine diphosphate; FdUMP: fluorodeoxyuridine monophosphate; FdUTP: fluorodeoxyuridine triphosphate; dUTPase: deoxyuridine pyrophosphatase; FTD: α,α,α-trifluorothymidine (trifluridine); FUDP: fluorouridine diphosphate; FUMP: fluorouridine monophosphate; FUR: fluorouridine; FUTP: fluorouridine phosphate; NDK: nucleoside diphosphate kinase; OPRT: orotate phosphoribosyltransferase; TK: thymidine kinase; TP: thymidine phosphorylase; TPI: tipiracil hydrochloride; TS: thymidylate synthase; UMP-CMPK: uridine monophosphate-cytidine monophosphate kinase; UP: uridine phosphorylase.