Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Mol Cancer Ther. 2020 Jun;19(6):1363-1372. doi: 10.1158/1535-7163.MCT-19-0918. Epub 2020 May 5.
Esophageal squamous cell carcinoma (ESCC) is a disease characterized by a high mutation rate of the 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 -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 and Thus, the combination of trifluridine/tipiracil and a CHK1 inhibitor exhibits effective antitumor effects, suggesting a novel therapeutic strategy for ESCC.
食管鳞状细胞癌 (ESCC) 是一种具有高基因突变率的疾病，该基因在 DNA 损伤反应 (DDR) 中发挥关键作用，并受检查点激酶 (CHK) 2 调节。CHK1 是另一种关键的 DDR 相关蛋白，其选择性抑制被认为对 -突变型癌症特别敏感，因为两条途径 (CHK1 和/或 CHK2-p53) 的缺失由于 DDR 的严重损伤而导致致命。这种治疗策略被称为合成致死性。在这里，我们提出了一种基于合成致死性的新的治疗策略，结合曲氟尿苷/替匹嘧啶和 prexasertib（CHK1 抑制剂）作为治疗 ESCC 的方法。曲氟尿苷是抗肿瘤药物曲氟尿苷/替匹嘧啶（曲氟尿苷降解抑制剂）的关键成分，也称为 TAS-102。在这项研究中，我们证明曲氟尿苷与 ESCC 细胞中的 CHK1 磷酸化增加相结合，降低 S 期比例并诱导 ssDNA 损伤。因为 CHK1 磷酸化被认为是曲氟尿苷介导的 DNA 损伤的 DDR 诱导，所以我们检查了 CHK1 抑制对曲氟尿苷治疗的影响。结果，短发夹 RNA 抑制 CHK1 或用 CHK1 抑制剂 prexasertib 处理，显著增强了曲氟尿苷介导的 DNA 损伤，表现为 γH2AX 表达增加。此外，曲氟尿苷/替匹嘧啶联合 CHK1 抑制显著抑制了 ESCC 来源的异种移植肿瘤的生长。此外，曲氟尿苷和 prexasertib 的联合增强了 ESCC 细胞的放射敏感性。因此，曲氟尿苷/替匹嘧啶和 CHK1 抑制剂的联合具有有效的抗肿瘤作用，为 ESCC 提供了一种新的治疗策略。
