Application of dopamine receptor antagonist inhibiting WNT-YAP/TAZ pathway for colon cancer treatment

• Project/Area Number: 16K18457
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Iwate Medical University
• Principal Investigator: Oku Yusuke 岩手医科大学, 薬学部, 講師 (50626843)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: YAP/TAZ / がん分子標的薬 / WNT/beta-catenin / 既存医薬品 / 癌 / シグナル伝達 / 薬学

Outline of Final Research Achievements

We originally identified WNT-beta catenin signal inhibitors including pimozide, a dopamine receptor antagonist. In this study, we found that these WNT-beta catenin inhibitors inhibits the nuclear translocation of transcriptional co-activator YAP/TAZ by WNT. Nuclear translocation of YAP/TAZ is facilitated by lysophosphatidic acid (LAP).However, WNT-beta catenin inhibitors including pimozide did not inihbit LAP-mediated nuclear translocation of YAP/TAZ. These results suggested that WNT-beta-catenin inhibitors which we identified preferentially inhibits WNT-mediated nuclear translocation of YAP/TAZ.

Research Products

• [Journal Article] Sensitisation of cancer cells to MLN8237, an Aurora-A inhibitor, by YAP/TAZ inactivation (2018)
  • Author(s): Yusuke Oku, Naoyuki Nishiya, Shuhei Sugiyama, Haruka Sato, Yoshimasa Uehara
  • Journal Title: Anticancer Research Volume: in press
  • Peer Reviewed
• [Journal Article] Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis (2018)
  • Author(s): Yusuke Oku, Naoyuki Nishiya, Takaaki Tazawa, Takaya Kobayashi, Nanami Umezawa, Yasuyo Sugawara, and Yoshimasa Uehara.
  • Journal Title: FEBS Open Bio Volume: in press Issue: 6 Pages: 1001-1012
  • DOI: 10.1002/2211-5463.12440
  • Peer Reviewed / Open Access
• [Journal Article] Dynamic Phenotypic Transition of Breast Cancer Cells In Vitro Revealed by Self-floating Cell Culture. (2017)
  • Author(s): Oku Y, Nishiya N, Tsuda K, Shibazaki M, Maesawa C, Uehara Y.
  • Journal Title: Anticancer Research Volume: 37 Issue: 4 Pages: 1793-1797
  • DOI: 10.21873/anticanres.11513
  • Peer Reviewed
• [Presentation] がん遺伝子産物YAPの不活性化は、Wee1キナーゼ阻害薬AZD1775に対する感受性を導く. (2017)
  • Author(s): 奥裕介、西谷直之、上原至雅
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] EGFR-TKIの副作用を回避する化合物の表現型基盤探索 (2017)
  • Author(s): 西谷 直之、奥 裕介、上原 至雅
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] L858R/T790M/C797S変異に有効なEGFRチロシンキナーゼ阻害剤 (2017)
  • Author(s): 福田 勉、石橋 郁人、岩尾 正倫、奥 裕介、西谷 直之、上原 至雅、旦 慎吾、矢守 隆夫
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Inactivation of YAP sensitizes ovarian cancer cells to MLN8237, an Aurora-A inhibitor, through p73-dependent apoptosis. (2017)
  • Author(s): Yusuke Oku, Naoyuki Nishiya, Yoshimasa Uehara.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Chemical suppression of adverse effects induced by EGFR tyrosine kinase inhibitors. (2017)
  • Author(s): Naoyuki Nishiya, Yusuke Oku, Yoshimasa Uehara.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 翻訳調節を介したWnt/β-catenin経路阻害と抗腫瘍作用 (2017)
  • Author(s): 西谷直之、米澤穂波、遠藤春香、奥裕介、上原至雅
  • Organizer: 日本薬学会第137回年会
  • Place of Presentation: 仙台
• [Presentation] EGFR-TKIによる副作用のモデル化と毒性緩和の分子戦略 (2016)
  • Author(s): 西谷直之、奥裕介、上原至雅
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府
• [Presentation] がん遺伝子産物YAPによるAurora-A kinase阻害剤MLN8237 (alisertib) 耐性の付与 (2016)
  • Author(s): 奥裕介、西谷直之、上原至雅
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府
• [Presentation] がん遺伝子産物YAP/TAZの不活性化は、卵巣がん細胞をAurora-A阻害剤に感受性化する (2016)
  • Author(s): 奥裕介、西谷直之、上原至雅
  • Organizer: 第76回日本癌学会学述総会
  • Place of Presentation: 横浜