Analysis of RRM1 inhibition regulating DNA damage repair signaling of Gemcitabine

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15267
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ono Hiroaki 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (60466901)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 膵臓癌 / ゲムシタビン / RRM1 / 抗癌剤耐性

Outline of Final Research Achievements

In this study, we analyzed RRM 1 expression in 121 pancreatic cancer surgeries performed at Tokyo Medical and Dental University and found a significant association between high RRM1 expression and poorer postoperative prognosis (OS p=0.006, DFS p=0.0491). In vitro experiments showed that gemcitabine-induced cytoplasmic upregulation of RRM1 in tumor cells was associated with the acquisition of drug resistance. In addition, RRM1 inhibition using siRNAs and hydroxyurea enhanced gemcitabine sensitivity in pancreatic cancer cells.
The result of this study was presented at medical conferences such as the 2020 Japanese Surgical Association and the Japan Digestive Disease Week and was accepted for publication in the journal, Plos ONE (Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells. Kato T, Ono H, Fujii M, Akahoshi K, Ogura T, Ogawa K, Ban D, Kudo A, Tanaka S, Tanabe M. PLoS One. 2021 Jun 10;16(6): e0252917).

Free Research Field

腫瘍外科

Academic Significance and Societal Importance of the Research Achievements

本研究によりRRM1遺伝子が膵臓癌における有効的な治療ターゲットであることが分かりました。またゲムシタビン投与後の耐性獲得におけるダイナミズムに関連していることが明らかとなりました。膵臓癌におけるキードラッグであるゲムシタビンの抗癌剤作用を増強させる新規治療薬として本研究で着目したRRM1などリボヌクレオチドリダクターゼ阻害剤による治療が有用であることが示されました。今後はRRM1阻害剤の臨床応用を企図したさらなる解析を行っていきます。