RRC ID 66859
Author Ohashi S, Kikuchi O, Nakai Y, Ida T, Saito T, Kondo Y, Yamamoto Y, Mitani Y, Nguyen Vu TH, Fukuyama K, Tsukihara H, Suzuki N, Muto M.
Title Synthetic Lethality with Trifluridine/Tipiracil and Checkpoint Kinase 1 Inhibitor for Esophageal Squamous Cell Carcinoma.
Journal Mol Cancer Ther
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.
Volume 19(6)
Pages 1363-1372
Published 2020-6-1
DOI 10.1158/1535-7163.MCT-19-0918
PII 1535-7163.MCT-19-0918
PMID 32371587
MeSH Animals Apoptosis Cell Proliferation Checkpoint Kinase 1 / antagonists & inhibitors* Checkpoint Kinase 1 / genetics Drug Combinations Esophageal Neoplasms / drug therapy Esophageal Neoplasms / genetics Esophageal Neoplasms / metabolism Esophageal Neoplasms / pathology* Esophageal Squamous Cell Carcinoma / drug therapy Esophageal Squamous Cell Carcinoma / genetics Esophageal Squamous Cell Carcinoma / metabolism Esophageal Squamous Cell Carcinoma / pathology* Humans Male Mice Mice, Hairless Mice, SCID Protein Kinase Inhibitors / pharmacology* Pyrrolidines / pharmacology* Synthetic Lethal Mutations* Thymine / pharmacology* Trifluridine / pharmacology* Tumor Cells, Cultured Xenograft Model Antitumor Assays
IF 5.615
Human and Animal Cells TE-1(RCB1894) TE-10(RCB2099) TE-11(RCB2100)