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Development of novel therapeutic and diagnostic methods for EGFR-mutated lung cancers

Research Project

Project/Area Number 19K07724
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionNational Institute of Health Sciences

Principal Investigator

Tsukumo Yoshinori  国立医薬品食品衛生研究所, 遺伝子医薬部, 主任研究官 (40469630)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsEGFR / 肺がん / エクソソーム / リボソームプロファイリング / バイオマーカー / 分子標的 / 分泌糖タンパク / 糖鎖修飾 / 複合体形成 / 耐性克服
Outline of Research at the Start

本研究では、申請者がEGFR変異細胞の翻訳プロファイリングで明らかにした3つのエクソソームタンパクと2つの新規翻訳産物に着目し、それらの生理機能や肺がん進展との関わりを明らかにしていくことで、EGFR肺がんの新たな診断法ならびに治療法の開発を目指す。

Outline of Final Research Achievements

In East Asia, epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is particularly predominant and leading cause of lung cancer death. We identified several proteins specifically upregulated in EGFR-mutated cells using ribosome profiling, which is a technology to measure genome-wide changes in protein production in cell. Of note, a secretory glycoprotein X, which is one of the upregulated proteins, contributed to the cell growth and proliferation of EGFR-mutated cancers but not EGFR-wildtype cells. Importantly, inhibition of the protein X using siRNA, CRISPR, and a specific blocking antibody decreases survival of cells resistant to EGFR tyrosine kinase inhibitors (TKIs). This study suggests the potential therapeutic advantages of targeting the protein X against EGFR-TKI resistant cells.

Academic Significance and Societal Importance of the Research Achievements

EGFR変異陽性肺がんは、日本人における肺腺がん全体の約半数を占める。現在、進行性肺がんを対象に、複数のEGRF阻害薬が肺がん治療薬として承認されているものの、それら薬剤への耐性化が問題となっている。本研究で見出したタンパクXは、EGFR変異陽性のがん細胞から豊富に分泌される特徴を有し、かつ、タンパクXの阻害はEGFR阻害薬耐性がん細胞の増殖を抑制することができた。そのため、タンパクXは、EGFR肺がんをより早い段階で発見するためのバイオマーカーや既存薬への耐性を克服するための新たな治療標的となる可能性を秘めている。本研究のさらなる発展により、肺がん患者を救う手立てとなることを期待したい。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (12 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (4 results) (of which Invited: 1 results) Book (1 results)

  • [Journal Article] Development of Gilteritinib-Based Chimeric Small Molecules that Potently Induce Degradation of FLT3-ITD Protein2022

    • Author(s)
      Ohoka Nobumichi、Suzuki Masanori、Uchida Takuya、Tsuji Genichiro、Tsukumo Yoshinori、Yoshida Masayuki、Inoue Takao、Demizu Yosuke、Ohki Hitoshi、Naito Mikihiko
    • Journal Title

      ACS Medicinal Chemistry Letters

      Volume: 13 Issue: 12 Pages: 1885-1891

    • DOI

      10.1021/acsmedchemlett.2c00402

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Development of a potent small-molecule degrader against oncogenic BRAFV600E protein that evades paradoxical MAPK activation.2022

    • Author(s)
      Ohoka N, Suzuki M, Uchida T, Tsukumo Y, Yoshida M, Inoue T, Ohki H, Naito M.
    • Journal Title

      Cancer Sci.

      Volume: 113 Issue: 8 Pages: 2828-2838

    • DOI

      10.1111/cas.15401

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Protocols for Synthesis of and the Methods to Evaluate the Anticancer Effects2021

    • Author(s)
      Tsukumo Yoshinori、Tsuji Genichiro、Yokoo Hidetomo、Shibata Norihito、Ohoka Nobumichi、Demizu Yosuke、Naito Mikihiko
    • Journal Title

      Methods Mol. Biol.

      Volume: 2365 Pages: 331-347

    • DOI

      10.1007/978-1-0716-1665-9_18

    • ISBN
      9781071616642, 9781071616659
    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line.2020

    • Author(s)
      Tsukumo Y, Naito M, Suzuki T.
    • Journal Title

      PLoS One

      Volume: 15 Issue: 3 Pages: 1-16

    • DOI

      10.1371/journal.pone.0229712

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Preparation of the standard cell lines for reference mutations in cancer gene-panels by genome editing in HEK 293T/17 cells.2020

    • Author(s)
      Suzuki T, Tsukumo Y, Furihata C, Naito M, Kohara A.
    • Journal Title

      Genes Environ

      Volume: 42 Issue: 1 Pages: 1-12

    • DOI

      10.1186/s41021-020-0147-2

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeted Protein Degradation by Chimeric Small Molecules, PROTACs and SNIPERs.2019

    • Author(s)
      Naito M, Ohoka N, Shibata N, Tsukumo Y.
    • Journal Title

      Front Chem.

      Volume: 7 Pages: 849-849

    • DOI

      10.3389/fchem.2019.00849

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer.2019

    • Author(s)
      Muller D, Shin S, Goullet de Rugy T, Samain R, Baer R, Strehaiano M, Masvidal-Sanz L, Guillermet-Guibert J, Jean C, Tsukumo Y, Sonenberg N, Marion F, Guilbaud N, Hoffmann JS, Larsson O, Bousquet C, Pyronnet S, Martineau Y.
    • Journal Title

      JCI Insight

      Volume: 4 Pages: 1-17

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Identification of protein X as a potential therapeutic target against EGFR-mutated cancers2022

    • Author(s)
      Yoshinori Tsukumo, Nobumichi Ohoka, Mikihiko Naito, Takayoshi Suzuki
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] コンパニオン診断薬の開発状況と規制2022

    • Author(s)
      築茂由則
    • Organizer
      化学工学会第53回秋季大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] EGFR 変異陽性肺がんに対する新規治療標的分子の同定2021

    • Author(s)
      築茂由則, 大岡伸通, 内藤幹彦, 鈴木孝昌
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] Translational profiling of EGFR-mutated cancer cells2019

    • Author(s)
      築茂由則、鈴木孝昌、内藤幹彦
    • Organizer
      日本癌学会
    • Related Report
      2019 Research-status Report
  • [Book] 次世代医薬とバイオ医療  第8章 個別化医療に向けた診断用医薬品 コンパニオン診断薬2022

    • Author(s)
      1.築茂由則, 井上貴雄
    • Total Pages
      16
    • Publisher
      東京化学同人
    • Related Report
      2021 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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