Abstract
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 and prexasertib (CHK1 inhibitor) as a treatment for ESCC. Trifluridine is a key component of the antitumor drug combination with trifluridine/tipiracil (an inhibitor of trifluridine degradation), also known as TAS-102. In this study, we demonstrate that trifluridine increases CHK1 phosphorylation in ESCC cells combined with a reduction of the S-phase ratio as well as the induction of ssDNA damage. Because CHK1 phosphorylation is considered to be induced as DDR for trifluridine-mediated DNA damage, we examined the effects of CHK1 inhibition on trifluridine treatment. Consequently, CHK1 inhibition by short hairpin RNA or treatment with the CHK1 inhibitor, prexasertib, markedly enhanced trifluridine-mediated DNA damage, represented by an increase of γH2AX expression. Moreover, the combination of trifluridine/tipiracil and CHK1 inhibition significantly suppressed tumor growth of ESCC-derived xenograft tumors. Furthermore, the combination of trifluridine and prexasertib enhanced radiosensitivity both in vitro and in vivo Thus, the combination of trifluridine/tipiracil and a CHK1 inhibitor exhibits effective antitumor effects, suggesting a novel therapeutic strategy for ESCC.
Highlights
Esophageal squamous cell carcinoma (ESCC) is the major histologic type of esophageal cancers [1], which are the seventh leading cause of cancer-related mortality and the eighth most common cancer worldwide [2]
Because checkpoint kinase 1 (CHK1) phosphorylation is considered to be induced as DNA damage response (DDR) for trifluridine-mediated DNA damage, we examined the effects of CHK1 inhibition on trifluridine treatment
We showed that trifluridine markedly increased CHK1 phosphorylation (S317 and S345) in ESCC cells
Summary
Esophageal squamous cell carcinoma (ESCC) is the major histologic type of esophageal cancers [1], which are the seventh leading cause of cancer-related mortality and the eighth most common cancer worldwide [2]. Despite recent progress in therapeutics, the prognosis of patients with ESCC remains poor [3,4,5]. The development of novel chemotherapeutic strategies is required to improve the outcomes of patients with ESCC. A novel therapeutic strategy targeting the DNA damage response (DDR) was reported [6, 7]. DDR is a critical mechanism that maintains genome stability [8], and it is coordinated by two distinct kinase signaling cascades: ataxia telangiectasia Rad3-related (ATR)-checkpoint kinase 1 (CHK1; ATR–CHK1) and ataxia tel-
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