Synthetic lethality with FTD and CHK1 inhibitor for esophageal squamous cell carcinoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kyoto University
• Principal Investigator: OHASHI SHINYA 京都大学, 医学研究科, 特定准教授 (20435556)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 食道扁平上皮癌 / CHK1シグナル阻害 / DNA修復応答 / トリフルリジン / 放射線感受性

Outline of Final Research Achievements

In this study, we revealed the DNA damage response when esophageal squamous cell carcinoma (ESCC) cells was treated with FTD, and found that FTD strongly induces CHK1 phosphorylation in ESCC cells. CHK1 inhibitors enhanced the FTD-induced DNA damage and/or cytotoxic effects in vitro. Furthermore, combination treatment with FTD and CHK1 inhibitors showed an efective antitumor effects on ESCC xenograft tumors as well as PDX tumors. Moreover, we showed that drug treatment with FTD and CHK1 inhibitors significantly enhances radiosensitivity, and the combination treatment with FTD, CHK1 inhibitor and radiotherapy showed a potent antitumor effects on ESCC.

Free Research Field

消化器内科

Academic Significance and Societal Importance of the Research Achievements

食道扁平上皮癌は集学的治療を行っても依然死亡率の高い難治性癌であり、食道扁平上皮癌の予後改善のためには有効性の高い抗がん剤治療の開発が急務である。本研究成果により、トリフルリジンとCHK1阻害剤の併用治療が食道扁平上皮癌細胞に対する新たな治療法となりうる可能性が示唆された。今後、臨床応用へ向けたさらなる研究開発が期待される。