Synthetic Lethality with Trifluridine/Tipiracil and Checkpoint Kinase 1 Inhibitor for Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a disease characterized by a high mutation rate of the TP53 gene, which plays pivotal roles in the DNA damage response (DDR) and is regulated by checkpoint kinase (CHK) 2. CHK1 is another key DDR-related protein, and its selective inhibition is suggested to be particularly sensitive to TP53-mutated cancers, because a loss of both pathways (CHK1 and/or CHK2-p53) is lethal due to the serious impairment of DDR. Such a therapeutic strategy is termed synthetic lethality. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil (FTD/TPI) and prexasertib (CHK1 inhibitor) as a treatment for ESCC. FTD is a key component of the antitumor drug combination with FTD/TPI (an inhibitor of FTD degradation), also known as TAS-102. In this study, we demonstrate that FTD increases CHK1-phosphorylation in ESCC cells combined with a reduction of the S-phase ratio as well as the induction of single-strand DNA damage. Because CHK1-phosphorylation is considered to be induced as DDR for FTD-mediated DNA damage, we examined the effects of CHK1-inhibition on FTD treatment. Consequently, CHK1-inhibition by shRNA or treatment with the CHK1 inhibitor, prexasertib, markedly enhanced FTD-mediated DNA damage, represented by an increase of gamma-H2AX expression. Moreover, the combination of FTD/TPI and CHK1-inhibition significantly suppressed tumor growth of ESCC-derived xenograft tumors. Furthermore, the combination of FTD and prexasertib enhanced radiosensitivity both in vitro and in vivo. Thus, the combination of FTD/TPI and a CHK1 inhibitor exhibits effective antitumor effects, suggesting a novel therapeutic strategy for ESCC.