• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular and clinical characterization of sensivity to SHP2 inhibition in KRAS-mutant cancers

Research Project

Project/Area Number 19K23909
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0901:Oncology and related fields
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Kano Yoshihito  東京医科歯科大学, 大学院医歯学総合研究科, 講師 (10633125)

Project Period (FY) 2019-08-30 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsKRAS / SHP2阻害 / Q61変異 / クリニカルシークエンス / チロシンリン酸化 / リキッドバイオプシー / 膵臓癌 / SHP2 / 分子標的治療 / がん個別化医療
Outline of Research at the Start

KRAS遺伝子はヒトがんの中で最も高頻度に変異しており膵臓癌、大腸癌、肺癌などの難治癌にその変異が多くみられる。しかし蛋白質の構造からKRAS自体を治療標的とすることは不可能とされている。近年我々はKRASが他のがん遺伝子であるSHP2から直接活性化を受ける新しい機序を発見し、SHP2を標的とすることでRASの働きを不活性化することを明らかとした。本研究ではSHP2とKRASの関係についてさらなる解析を加え標的治療の可能性を探るとともに、KRASの変異型によるSHP2阻害剤の感受性を網羅的に解析することにより、将来的には個別化医療へと応用することを目指す。

Outline of Final Research Achievements

KRAS mutations are found in some of the most aggressive and deadly cancers, including up to 25% of lung cancers to and over 90% of pancreatic cancers. A recent series of reports suggest that SHP2 inhibition (SHP2i) is effective to KRAS-mutated cancers including non-small cell lung and pancreatic cancers. Here, we report that lung and pancreatic cancer cells that harbor KRAS Q61H mutation are uniquely resistant to SHP2i. Our biochemical studies show that the Q61H mutation has negligible impact on binding to BRAF-RBD. Whereas phosphorylation of WT and G12 mutants impairs binding to BRAF-RBD, the uncompromised ability of phosphorylated KRAS Q61H to activate MAPK signaling is retained. The independence of KRAS Q61H from the stimulatory roles of SHP2 in reversing Src phosphorylation confers resistance to SHP2i. Together these insights provide an unprecedented mechanistic understanding of oncogenic KRAS mutants that can guide clinical trials of SHP2i for cancer patients bearing KRAS Q61H.

Academic Significance and Societal Importance of the Research Achievements

SHP2は脱リン酸化酵素として初のがん遺伝子であり、機序は不明ながらKRASシグナルに深く関与する一方で、KRASと同様に長らくundruggable targetと考えられていた。しかし近年SHP2に対する低用量かつ経口投与可能な薬剤が開発されている。今回申請者はKRASとSHP2を直接関連づけるメカニズムとしてKRASリン酸化モデルを提唱した。さらに特定の変異型に対するSHP2阻害の感受性の違いを明らかとした。SHP2阻害剤は現在Phase I試験中であるがKRAS変異型による感受性の差を考慮した臨床試験のデザインが必要であり、今後への提言としたい。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (24 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 5 results) Presentation (12 results) (of which Invited: 2 results)

  • [Int'l Joint Research] University of Toronto/University Health Network/Black Diamond Therapeutics(カナダ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] University of Toronto/University Health Network(カナダ)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] University of Toronto/University Health Network(カナダ)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Clinical utility of comprehensive genomic profiling in Japan: Result of PROFILE-F study2022

    • Author(s)
      Aoyagi Yasuko、Kano Yoshihito et.al
    • Journal Title

      PLOS ONE

      Volume: 17 Issue: 3 Pages: 0266112-0266112

    • DOI

      10.1371/journal.pone.0266112

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MYC-PDL1 axis reduces sensitivity to nivolumab in recurrent head and neck squamous cell carcinoma2022

    • Author(s)
      Noji Rika、Kano Yoshihito、Hirai Hideaki、Onishi Iichiroh、Nishii Naoto、Yoshimura Ryoichi、Miyake Satoshi、Ikeda Sadakatsu、Harada Hiroyuki
    • Journal Title

      Oral Oncology

      Volume: 124 Pages: 105666-105666

    • DOI

      10.1016/j.oraloncology.2021.105666

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Primary pulmonary choriocarcinoma with a genomic sequence2021

    • Author(s)
      Onishi Iichiroh、Kirimura Susumu、Wakejima Ryo、Okubo Kenichi、Odai Tamami、Kakuta Ryota、Kano Yoshihito、Ikeda Sadakatsu、Akashi Takumi、Kitagawa Masanobu
    • Journal Title

      Pathology International

      Volume: 72 Issue: 2 Pages: 141-143

    • DOI

      10.1111/pin.13193

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors2021

    • Author(s)
      Gebregiworgis Teklab, Kano Yoshihito et. al
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1

    • DOI

      10.1038/s41467-021-26526-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ASO Author Reflections: Impact of Liquid Biopsy Using Plasma Cell-Free DNA in Solid Tumors in Japan2021

    • Author(s)
      Matsudera Shotaro、Kano Yoshihito、Ikeda Sadakatsu
    • Journal Title

      Annals of Surgical Oncology

      Volume: 28 Issue: 13 Pages: 8506-8507

    • DOI

      10.1245/s10434-021-09858-3

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study)2021

    • Author(s)
      Matsudera S、Kano Y、Aoyagi Y、Tohyama K、Takahashi K、Kumaki Y、Mitsumura T、Kimura K、Onishi I、Takemoto A、Ban D、Ono H、Kudo Atsushi、et.al.
    • Journal Title

      Annals of Surgical Oncology

      Volume: - Issue: 13 Pages: 697-706

    • DOI

      10.1245/s10434-021-09856-5

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells2021

    • Author(s)
      Liotti Federica、Kumar Narender、Prevete Nella、Marotta Maria、Sorriento Daniela、Ieran? Caterina、Ronchi Andrea、Marino Federica Zito、Moretti Sonia、Colella Renato、Puxeddu Efiso、Paladino Simona、Kano Yoshihito、Ohh Michael、Scala Stefania、Melillo Rosa Marina
    • Journal Title

      Journal of Experimental & Clinical Cancer Research

      Volume: 40 Issue: 1 Pages: 22-22

    • DOI

      10.1186/s13046-020-01818-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intestinal phenotype is maintained by Atoh1 in the cancer region of intraductal papillary mucinous neoplasm2020

    • Author(s)
      Katsukura Nobuhiro、Watanabe Sho、Shirasaki Tomoaki、Hibiya Shuji、Kano Yoshihito、Akahoshi Keiichi、Tanabe Minoru、Kirimura Susumu、Akashi Takumi、Kitagawa Masanobu、Okamoto Ryuichi、Watanabe Mamoru、Tsuchiya Kiichiro
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 2 Pages: 932

    • DOI

      10.1111/cas.14755

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] NRAS Status Determines Sensitivity to SHP2 Inhibitor Combination Therapies Targeting the RAS-MAPK Pathway in Neuroblastoma2020

    • Author(s)
      Valencia-Sama Ivette、Ladumor Yagnesh、Kee Lynn、Adderley Teresa、Christopher Gabriella、Robinson Claire M.、Kano Yoshihito、Ohh Michael、Irwin Meredith S.
    • Journal Title

      Cancer Research

      Volume: 80 Issue: 16 Pages: 3413-3423

    • DOI

      10.1158/0008-5472.can-19-3822

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 進行肝癌に対するがんゲノム診療における臨床的問題点とリアルワールドデータ解析2021

    • Author(s)
      加納嘉人、朝比奈靖浩、岡本隆一
    • Organizer
      第108回 日本消化器病学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 肝内胆管癌の臨床的問題点と網羅的がんゲノム解析の有用性検討2021

    • Author(s)
      加納嘉人、北畑富貴子、村川美也子、柿沼晴、東正新、中川美奈、 井津井康浩、新田沙由梨、三好正人、田邉稔、三宅智、池田貞勝、 岡本隆一、朝比奈靖浩
    • Organizer
      第57回肝癌研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] がんゲノム解析によりニボルマブ耐性機構が示唆された再発頬粘膜癌の一例2021

    • Author(s)
      野地理夏,加納嘉人,平井秀明,山下大和,工藤亮,富岡寛文,島本裕彰,道泰之,大西威一郎,三浦雅彦,吉村亮一,三宅智,池田貞勝,原田浩之
    • Organizer
      第45回日本頭頸部癌学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] KRAS Q61H mutation evades the regulation of tyrosyl phosphorylation and renders cancer cells resistant to SHP2 inhibitor.2020

    • Author(s)
      YOSHIHITO KANO, Teklab Gebregiworgis, Christopher Marshall, Mitsuhiko Ikura, Satoshi Miyake, Michael Ohh.
    • Organizer
      第18回日本臨床腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Detection of RAS mutation in solid cancers using NGS-based genome profiling tests.2020

    • Author(s)
      加納嘉人、野地理夏、山下大和、工藤亮、大西威一郎、谷本幸介、宮冬樹、中川剛士、石川敏昭、植竹宏之、絹笠祐介、田邉稔、朝蔭孝宏、原田浩之、岡本隆一、三宅智、池田貞勝
    • Organizer
      第18回日本臨床腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Clinical utility of tumor-profiling multiplex gene panel testing in advanced head and neck cancer at TMDU.2020

    • Author(s)
      加納 嘉人,野地 理夏, 山下 大和, 工藤 亮, 田崎 彰久, 大野 十央, 有泉 陽介, 平井 秀明, 富岡 寛文, 島本 裕彰, 道 泰之, 三浦 雅彦, 吉村 亮一, 朝蔭 孝宏, 原田 浩之, 岡本 隆一, 三宅 智, 池田 貞勝
    • Organizer
      第18回日本臨床腫瘍学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 進行肝細胞癌に対するがんゲノム診療における網羅的遺伝子パネル検査の有用性とバイオマーカー探索.2020

    • Author(s)
      加納嘉人、北畑富貴子、村川美也子、柿沼晴、東正新、中川美奈、 井津井康浩、新田沙由梨、三好正人、青柳康子、松寺翔太郎、遠山皓基、 田邉稔、三宅智、池田貞勝、朝比奈靖浩.
    • Organizer
      第56回日本肝癌研究会
    • Related Report
      2020 Research-status Report
  • [Presentation] Evasion of KRASQ61H regulation by tyrosine phosphorylation renders cancer cells resistant to SHP2 inhibitor.2020

    • Author(s)
      Yoshihito Kano, Teklab Gebregiworgis, Christopher B. Marshall, Mitsuhiko Ikura, Michael Ohh.
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Inhibition of SHP2 promotes the tyrosyl phosphorylation of KRAS and suppresses the pancreatic cancer growth.2019

    • Author(s)
      Yoshihito Kano, Teklab Gebregiworgis, Christopher Marshall,Mitsuhiko Ikura, Michael Ohh
    • Organizer
      第78回日本癌学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] KRASチロシンリン酸化モデルに基づく膵癌新規分子機構と治療戦略2019

    • Author(s)
      加納嘉人,Teklab Gebregiworgis, Christopher Marshall, 伊倉 光彦, Michael Ohh.
    • Organizer
      第17回日本臨床腫瘍学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] チロシンリン酸化モデルに基づくKRAS制御機構の解明と治療応用の可能性.2019

    • Author(s)
      加納嘉人
    • Organizer
      大阪大学蛋白質研究所セミナー「がん研究の新機軸」
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Drugging the Undruggable ~新規分子標的治療による難治癌克服への挑戦~.2019

    • Author(s)
      加納嘉人
    • Organizer
      第25回東京西部消化器先端医療勉強会
    • Related Report
      2019 Research-status Report
    • Invited

URL: 

Published: 2019-09-03   Modified: 2023-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi