Identification of sentization markers and elucidation of drug resistance mechanism for a CK2 inhibitor on cholangiocarcinoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08449
• 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: Nagoya City University
• Principal Investigator: Miyabe Katsuyuki 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (00543985)
• Co-Investigator(Kenkyū-buntansha): 吉田 道弘 名古屋市立大学, 医薬学総合研究院(医学), 講師 (20636328)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 胆管癌 / Silmitasertib / CK2阻害薬 / 薬剤抵抗性

Outline of Final Research Achievements

Exome sequencing was performed on DNA extracted from xenografts obtained from mice treated with Silmitasertib and GEM+CDDP, mice treated with GEM+CDDP, and control mice. Differences such as genetic mutations were investigated, and gene amplification of PGLYRP2 and PCDH86 was also revealed in the comparison between GEM+CDDP and GEM+CDDP+Silmitasertib. Although attempts were made to create drug-resistant strains for in vitro experiments, they have been unsuccessful so far. Therefore, further analysis based on data obtained from in vivo specimens will be continued to elucidate the mechanism of drug resistance.

Free Research Field

消化器内科　胆道・膵臓分野

Academic Significance and Societal Importance of the Research Achievements

CK2阻害剤Silmitasertibの薬剤抵抗性獲得に寄与する機序を検討した。すでにSilmitasertibを投与されたサンプルおよび投与されていないサンプルとの比較をすることにより、薬剤耐性に関わる遺伝子を探り出すことができた。Silmitasertibは近年胆管癌の治療に有望な分子標的薬として注目されており、一部の胆管癌患者の予後を延長するものと期待されている。その薬剤耐性機序を探るうえでのヒントを見つけ出すことにより、本阻害剤が実際の患者に投与され、耐性となった際の次の治療戦略を考える上で、本研究が重要な意義を果たすものと思われる。