Elucidation of molecular mechanisms of resistance to MAP kinase inhibitor in pancreatic cancer and establishment of novel therapeutic strategy targeting to the resistance

• Project/Area Number: 18K06992
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Oita University
• Principal Investigator: Moriyama Masatsugu 大分大学, 医学部, 教授 (90239707)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵癌 / MAPキナーゼ阻害薬 / 耐性機序 / 耐性機構 / Clusterin / MAPキナーゼ / 阻害薬 / 耐性

Outline of Final Research Achievements

It has been shown that an activated MAP kinase contributes to maintain the higher levels of cell growth potential and invasiveness in pancreatic cancer. Therefore, an inhibitor to the MAP kinase is expected to be a promising agent against the pancreatic cancer. However, to date, several clinical trials have failed to demonstrate the efficacy of MAP kinase inhibitor to the patients with pancreatic cancer. In this study, we showed that Clusterin, expressed in pancreatic cancer cells, was involved in the increased cell viability and the resistance to MAP kinase inhibitor. Furthermore, we exhibited the synergistic suppressive effects on cell growth by combination of the treatment with MAP kinase inhibitor and downregulation of Clusterin.

Academic Significance and Societal Importance of the Research Achievements

膵癌は最も予後不良な癌のひとつである。その理由として、顕著な有効性を示す抗がん剤治療法が開発されていないことが挙げられる。したがって膵癌の治療成績を改善するためには、膵癌の発症・進展に関わる分子メカニズムを解明して、その知見に基づく新規治療法の開発が強く望まれる。
本研究では、MAPキナーゼ阻害薬抵抗性獲得に関与する分子Clusterinを同定した。さらに、Clusterinを標的とした治療を併用することでMAPキナーゼ阻害薬の有効性が回復することを示した。今後、ClusterinとMAPキナーゼを標的とする新規膵癌治療法の確立を目指す。

Research Products

• [Journal Article] A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism. (2020)
  • Author(s): Nakada C, Hijiya N, Tsukamoto Y, Yano S, Kai T, Uchida T, Kimoto M, Takahashi M, Daa T, Matsuura K, Shin T, Mimata H, Moriyama M.
  • Journal Title: J Pathol. Volume: in press Issue: 1 Pages: 12-25
  • DOI: 10.1002/path.5394
  • Peer Reviewed
• [Journal Article] DUSP4 is involved in the enhanced proliferation and survival of DUSP4-overexpressing cancer cells. (2020)
  • Author(s): Ratsada P, Hijiya N, Hidano S, Tsukamoto Y, Nakada C, Uchida T, Kobayashi T, Moriyama M.
  • Journal Title: Biochem Biophys Res Commun Volume: 528 Issue: 3 Pages: 586-593
  • DOI: 10.1016/j.bbrc.2020.05.140
  • Peer Reviewed / Open Access
• [Journal Article] S6 ribosomal protein phosphorylation is associated with malignancy of intraductal papillary mucinous neoplasm of the pancreas. (2020)
  • Author(s): Hirashita T, Hirashita Y, Iwashita Y, Endo Y, Kiyonaga M, Matsumoto S, Hijiya N, Moriyama M, Murakami K, Inomata M.
  • Journal Title: Ann Gastroenterol Surg Volume: 4 Issue: 5 Pages: 571-579
  • DOI: 10.1002/ags3.12367
  • Peer Reviewed / Open Access
• [Journal Article] Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1 (2018)
  • Author(s): Iwasaki K, Ninomiya R, Shin T, Nomura T, Kajiwara T, Hijiya N, Moriyama M, Mimata H, Hamada F
  • Journal Title: Cancer Science Volume: 109 Issue: 10 Pages: 3159-3170
  • DOI: 10.1111/cas.13754
  • Peer Reviewed / Open Access
• [Journal Article] Complete Sequences of the Human T-Cell Leukemia Virus Type 1 Proviral Genomes from Newly Established Adult T-Cell Leukemia Cell Lines in Oita Prefecture, Japan (2018)
  • Author(s): Fukumoto T, Ikebe E, Ogata M, Kohno K, Kuramitsu M, Sato Y, Fife N, Matsumoto T, Yahiro T, Ikeda M, Kusano S, Okayama A, Hori M, Hijiya N, Tsukamoto Y, Hirashita Y, Moriyama M, Ahmed K, Hasegawa H, Nishizono A, Saito M, Iha H
  • Journal Title: Genome Announcements Volume: 6 Issue: 25
  • DOI: 10.1128/genomea.00090-18
  • Peer Reviewed / Open Access
• [Journal Article] Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation (2018)
  • Author(s): Abe I, Teshima Y, Kondo H, Kaku H, Kira S, Ikebe Y, Saito S, Fukui A, Shinohara T, Yufu K, Nakagawa M, Hijiya N, Moriyama M, Shimada T, Miyamoto S, Takahashi N
  • Journal Title: Heart Rhythm Volume: 15 Issue: 11 Pages: 1717-1727
  • DOI: 10.1016/j.hrthm.2018.06.025
  • Peer Reviewed
• [Presentation] ZNF395の発現低下は膵癌の増殖能亢進と進展に寄与する (2020)
  • Author(s): 黒木 秀作, 泥谷 直樹, 塚本 善之, 中田 知里, 猪股 雅史, 小林 隆志, 守山 正胤
  • Organizer: 第79回日本癌学会総会
• [Presentation] 食道扁平上皮癌及び腺癌の機能比較モデルの作製 (2020)
  • Author(s): 柴田 智隆, 塚本 善之, 黒木 秀作, 矢野 信次, 錦 耕平, 鈴木 浩輔, 麓 祥一, 衛藤 剛, 守山 正胤, 猪股 雅史
  • Organizer: 第58回日本癌治療学会学術集会
• [Presentation] 大腸癌におけるDUSP4発現パターンとその意義について (2019)
  • Author(s): 一万田 充洋, 泥谷 直樹, 赤木 智徳, 白下 英史, 衛藤 剛, 猪股 雅史, 守山 正胤
  • Organizer: 第74回日本大腸肛門病学会学術集会
• [Presentation] RAS/BRAF変異型進行大腸癌における早期反応性マーカーを用いたtrametinib感受性予測法の検討 (2019)
  • Author(s): 平下 有香, 水上 一弘, 沖本 忠義, 兒玉 雅明, 白下 英史, 猪股 雅史, 守山 正胤, 村上 和成
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] 大腸癌におけるDUSP4発現変動の意義 (2018)
  • Author(s): 一万田 充洋, 泥谷 直樹, 赤木 智徳, 白下 英史, 衛藤 剛, 猪股 雅史, 守山 正胤
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 大腸癌におけるDUSP4発現低下は増殖能および浸潤能を亢進させる (2018)
  • Author(s): 泥谷 直樹, 一万田 充洋, 塚本 善之, 内田 智久, 中田 知里, 赤木 智徳, 衛藤 剛, 伊波 英克, 猪股 雅史, 守山 正胤
  • Organizer: 第107回日本病理学会総会