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Identification of intracellular activation sites of mutated tyrosine kinases in tumor cells and drug development based on the cellular localization

Research Project

Project/Area Number 16H05419
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionNational Cancer Center Japan

Principal Investigator

Nishida Toshirou  国立研究開発法人国立がん研究センター, 中央病院, 病院長 (40263264)

Co-Investigator(Kenkyū-buntansha) 小幡 裕希  国立研究開発法人国立がん研究センター, 研究所, ユニット長 (20609408)
黒川 量雄  国立研究開発法人理化学研究所, 光量子工学研究センター, 専任研究員 (40333504)
眞鍋 史乃  国立研究開発法人理化学研究所, 開拓研究本部, 専任研究員 (60300901)
安永 正浩  国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (80450576)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
KeywordsGIST / Kit / 分子標的薬 / イマチニブ / 細胞内分布 / 消化管間質細胞腫 / Kitチロシンキナーゼ / ゴルジ体 / 細胞内イメージング / Drug-Delivery System / 薬物動態 / 消化管間質腫瘍 / 分子標的治療薬 / 標的治療薬 / 薬剤耐性 / チロシンキナーゼ / DDS / KIT / 分子標的治療
Outline of Final Research Achievements

Mutated KIT tyrosine kinase, a major cause of gastrointestinal stromal tumor (GIST), mainly locates in the Golgi apparatus and activates downstream kinases. The KIT protein accumulated and activated in the Golgi apparatus is newly synthesized in ER and is transferred to the Golgi, and its Golgi accumulation appears to depend on the activation of KIT kinase. On the contrary, imatinib, a specific inhibitor of KIT tyrosine kinase, is indicated to be piled up in the secondary lysosomes using imatinib modified with fluorescents (NBD, BODIPY) or antibody to imatinib. Detailed analysis suggests that imatinib- fluorescents locate on the outer lysosomal membrane. These results indicate that the subcellular distribution of the target (KIT) and its inhibitor (imatinib) do not always harmonized with, suggesting room for improvement of the molecularly-targeted agents.

Academic Significance and Societal Importance of the Research Achievements

GISTの原因であるKIT遺伝子変異に伴うKITキナーゼ変異体がゴルジに集積し、ゴルジでのみ自己活性化し、増殖シグナルを出しており、新規に合成された(変異)KITのER⇒ゴルジ体の輸送を阻害することで、イマチニブ感受性株も耐性株も増殖抑制され、細胞死に至る発見は、分子標的薬に耐性になったドライバー遺伝子変異をもつがん腫治療に新しい方法論の道筋を示した。同時に、自己活性化した変異KITと阻害剤イマチニブが、細胞内で不均等分布を示すことは、ドライバー遺伝子変異に対し開発された、或いは、開発段階にある標的治療薬の細胞内分布の重要性を示唆するものである。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (32 results)

All 2019 2018 2017 2016 2015

All Journal Article (19 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Open Access: 14 results,  Acknowledgement Compliant: 2 results) Presentation (13 results) (of which Int'l Joint Research: 5 results,  Invited: 4 results)

  • [Journal Article] Defining Tumor Rupture in Gastrointestinal Stromal Tumor.2019

    • Author(s)
      Nishida T, Holmebakk T, Raut CP, Rutkowski P.
    • Journal Title

      Ann Surg Oncol.

      Volume: - Issue: 6 Pages: 1669-1675

    • DOI

      10.1245/s10434-019-07297-9

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting.2019

    • Author(s)
      Yamaguchi K, Komatsu Y, Satoh T, Uetake H, Yoshino T, Nishida T, Yamazaki N, Takikawa H, Morimoto T, Chosa M, Sunaya T, Hamada Y, Muro K, Sugihara K.
    • Journal Title

      Oncologist

      Volume: - Issue: 7 Pages: 450-457

    • DOI

      10.1634/theoncologist.2018-0377

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Visualization of secretory cargo transport within the Golgi apparatus2019

    • Author(s)
      Kurokawa K, Osakada H, Kojidani T, Waga M, Suda Y, Asakawa H, Haraguchi T, Nakano A.
    • Journal Title

      J. Cell Biol.

      Volume: - Issue: 5 Pages: 1602-1618

    • DOI

      10.1083/jcb.201807194

    • NAID

      120007133506

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diagnosis and Features of Ruptured GISTs in Clinical Practice.2019

    • Author(s)
      Nishida T.
    • Journal Title

      Ann Surg Oncol.

      Volume: 25 Issue: S3 Pages: 922-923

    • DOI

      10.1245/s10434-018-7026-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Roles of Designated Core Hospitals and Cooperative Hospitals for Cancer Genomic Medicine in Japan.2018

    • Author(s)
      Nishida T.
    • Journal Title

      Gan To Kagaku Ryoho

      Volume: 45 Pages: 1223-1227

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Clinicopathological features and prognosis of primary GISTs with tumor rupture in the real world.2018

    • Author(s)
      Nishida T, Cho H, Hirota S, Masuzawa T, Chiguchi G, Tsujinaka T, Kinki GIST Study Group
    • Journal Title

      Ann Surg Oncol.

      Volume: 25 Issue: 7 Pages: 1961-1969

    • DOI

      10.1245/s10434-018-6505-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3K signaling.2018

    • Author(s)
      Sugase T, Takahashi T, Serada S, Fujimoto M, Ohkawara T, Hiramatsu K, Nishida T, Hirota S, Saito Y, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Nakajima K, Hanasaki K, Kishimoto T, Mori M, Doki Y, Naka T.
    • Journal Title

      Gastric Cancer.

      Volume: epub Issue: 6 Pages: 968-976

    • DOI

      10.1007/s10120-018-0822-1

    • NAID

      40021694606

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The ER exit sites are specialized ER zones for the transport of cargo proteins from the ER to the Golgi apparatus2018

    • Author(s)
      Kurokawa Kazuo、Nakano Akihiko
    • Journal Title

      The Journal of Biochemistry

      Volume: 165 Issue: 2 Pages: 109-114

    • DOI

      10.1093/jb/mvy080

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mass spectrometry imaging for early discovery and development of cancer drugs.2018

    • Author(s)
      Yasunaga M, Manabe S, Furuta M, Ogata K, Koga Y, Takashima H, Nishida T, Matsumura Y.
    • Journal Title

      AIMS Med Sci.

      Volume: 5 Issue: 2 Pages: 162-180

    • DOI

      10.3934/medsci.2018.2.162

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 小胞体からゴルジ体へのタンパク質選別輸送2018

    • Author(s)
      黒川量雄
    • Journal Title

      生体の科学

      Volume: 69 Pages: 532-535

    • Related Report
      2018 Annual Research Report
  • [Journal Article] 小胞体からゴルジ体への分子輸送機構2018

    • Author(s)
      黒川量雄、中野明彦
    • Journal Title

      細胞

      Volume: 50 Pages: 420-423

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal stromal tumours.2018

    • Author(s)
      Obata Y, Horikawa K, Shiina I, Takahashi T, Murata T, Tasaki Y, Suzuki K, Yonekura K, Esumi H, Nishida T, Abe R
    • Journal Title

      Cancer Lett.

      Volume: 415 Pages: 1-10

    • DOI

      10.1016/j.canlet.2017.11.032

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Downregulation of miR-186 is associated with metastatic recurrence of gastrointestinal stromal tumors.2017

    • Author(s)
      Niinuma T, Kai M, Kitajima H, Yamamoto E, Harada T, Maruyama R, Nobuoka T, Kanda T, Hasegawa T, Tokino T, Sugai T, Shimomura Y, Nakase H, Suzuki H
    • Journal Title

      Oncology Letters

      Volume: 14 Pages: 5703-5710

    • DOI

      10.3892/ol.2017.6911

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MiR-199a Inhibits Secondary Envelopment of Herpes Simplex Virus-1 Through the Downregulation of Cdc42-specific GTPase Activating Protein Localized in Golgi Apparatus2017

    • Author(s)
      2.Kobayashi, K., Suemasa, F., Sagara, H., Nakamura, S., Ino, Y., Kobayashi, K., Hiramatsu, H., Haraguchi, T., Kurokawa, K., Todo, T., Nakano, A., and Iba, H.
    • Journal Title

      Scientific Reports,

      Volume: 7 Issue: 1 Pages: 6650-6650

    • DOI

      10.1038/s41598-017-06754-3

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells2017

    • Author(s)
      Hara, Y., Obata, Y., Horikawa, K., Tasaki, Y., Suzuki, K., Murata, T., Shiina, I. & Abe, R.
    • Journal Title

      PLoS ONE

      Volume: - Issue: 4 Pages: e0175514-e0175514

    • DOI

      10.1371/journal.pone.0175514

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors.2017

    • Author(s)
      Takahashi T, Elzawahry A, Mimaki S, Furukawa E, Nakatsuka R, Nakamura H, Nishigaki T, Serada S, Naka T, Hirota S, Shibata T, Tsuchihara K, Nishida T, Kato M.
    • Journal Title

      Genes Chromosomes Cancer.

      Volume: 56 Issue: 4 Pages: 303-313

    • DOI

      10.1002/gcc.22438

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Appropriate Follow-Up Strategies for Gastrointestinal Stromal Tumor Patients Based on the Analysis of Recurrent Interval and Patterns.2017

    • Author(s)
      Wada N, Takahashi T, Kurokawa Y, Nakajima K, Masuzawa T, Nakatsuka R, Kawada J, Nishida T, Kimura Y, Tanaka K, Miyazaki Y, Makino T, Yamasaki M, Takiguchi S, Mori M, Doki Y.
    • Journal Title

      Digestion

      Volume: 95 Issue: 2 Pages: 115-121

    • DOI

      10.1159/000452656

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Asian Consensus Guidelines for the Diagnosis and Management of Gastrointestinal Stromal Tumor.2016

    • Author(s)
      Koo DH, Ryu MH, Kim KM, Yang HK, Sawaki A, Hirota S, Zheng J, Zhang B, Tzen CY, Yeh CN, Nishida T, Shen L, Chen LT, Kang YK.
    • Journal Title

      Cancer Res Treat

      Volume: 48 Issue: 4 Pages: 1155-1166

    • DOI

      10.4143/crt.2016.187

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I.2015

    • Author(s)
      Nishida T, Tsujimoto M, Takahashi T, Hirota S, Blay J-V, Wataya-Kaneda M.
    • Journal Title

      J Gastroenterol

      Volume: s00535 Issue: 6 Pages: 1132-6

    • DOI

      10.1007/s00535-015-1132-6

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] 変異型Kitチロシンキナーゼのゴルジ体への異常局在とそこから発信される増殖シグナル ~ GIST・急性骨髄性白血病におけるオルガネラ シグナル ~2019

    • Author(s)
      小幡裕希, 原 泰志, 椎名 勇, 村田貴嗣, 津川 翔, 山脇康平, 高橋 剛, 岡本康司, 西田俊朗, 安部 良
    • Organizer
      第71回 日本細胞生物学会大会 (日本蛋白質科学会合同大会)
    • Related Report
      2018 Annual Research Report
  • [Presentation] 小胞体における積荷タンパク質選別輸送ゾーンの解析2018

    • Author(s)
      黒川量雄, Manuel Muniz, 中野明彦
    • Organizer
      酵母遺伝学フォーラム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Visualization of GPI-anchored proteins sorting in the ER2018

    • Author(s)
      Kurokawa K, Ikeda A, Funato K, Muniz M, Nakano A.
    • Organizer
      第70回 日本細胞生物学会・日本発生生物学会合同大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 小胞体における積荷タンパク質選別機構2018

    • Author(s)
      黒川量雄, Manuel Muniz, 中野明彦
    • Organizer
      第91回 日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 出芽酵母をモデルとした4Dイメージングで迫る真核生物の膜交通2018

    • Author(s)
      黒川量雄
    • Organizer
      酵母細胞研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Clinicopathological features of wild-type GISTs based on multiple-gene panel analysis2018

    • Author(s)
      Toshirou Nishida, Yoichi Naito, Yoshitaka Honma, Tsuyoshi Takahashi, Takuro Saito, Hitoshi Ichikawa
    • Organizer
      ESMO Asia
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] International Collaboration in Cancer2018

    • Author(s)
      Toshirou Nishida
    • Organizer
      Seoul International Cancer Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Wide field video-rate two-photon imaging by using spinning disk beam scanner2018

    • Author(s)
      Yasuhiro Maeda、Kazuo Kurokawa、Yoko Ito、Akihiko Nakano、Satsoshi Wada
    • Organizer
      SPIE Photonics West BiOS 2018
    • Related Report
      2017 Annual Research Report
  • [Presentation] New Interventions in GIST2017

    • Author(s)
      Toshirou Nishida
    • Organizer
      12th International Gastric Cancer Congress
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] マスト細胞白血病・GISTを無限増殖に導くKitチロシンキナーゼのがんシグナルは細胞膜ではなくオルガネラから発信される.2017

    • Author(s)
      小幡裕希, 堀川啓太, 原 泰志, 椎名 勇, 江角浩安, 西田俊朗, 安部 良
    • Organizer
      第69回 日本細胞生物学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 4D Imaging of Cargo Delivery in Maturating Golgi Cisternae in S. cerevisiae.2017

    • Author(s)
      Kazuo Kurokawa
    • Organizer
      Molecular Membrane Biology. Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Registry and Biobank for Rare Cancer in Japan:Gastrointestinal Stromal Tumor,Sarcoma and Neuroendocrine Tumor2016

    • Author(s)
      Toshirou Nishida
    • Organizer
      2nd Taiwan-Japan AROworkshop
    • Place of Presentation
      Taipei(台湾)
    • Year and Date
      2016-05-27
    • Related Report
      2016 Annual Research Report
  • [Presentation] Laparoscopic resection for SET near pyloric ring or GEJ2016

    • Author(s)
      Toshirou Nishida
    • Organizer
      KINGCA WEEK 2016
    • Place of Presentation
      ソウル(韓国)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2016-04-21   Modified: 2020-03-30  

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