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Study of osimertinib resistance mechanism against EGFR-positive lung adenocarcinoma using PDX model

Research Project

Project/Area Number 18K08141
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionKanazawa University

Principal Investigator

Kita Kenji  金沢大学, がん進展制御研究所, 特任助手 (80625252)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
KeywordsPDX / 肺がん / EGFR変異 / Osimertinib / オシメルチニブ耐性 / EGFR変異肺がん / オシメルチニブ / EGFR変異肺癌 / 肺腺癌 / SHOマウス / EGFR-TKI / 分子標的薬耐性 / MET増幅 / 肺腺がん / 耐性変異 / 肺癌
Outline of Final Research Achievements

A PDX model was established in 3 patients diagnosed with lung adenocarcinoma. We compared the tumors engrafted with surgically resected tumors (SRT) and PDX models by H & E staining and immunostaining, and confirmed that the histological type (degree of differentiation, interstitial mass) was maintained. In case # 11, treatment with osimertinib was so successful that we were unable to induce resistance because the tumor disappeared. On the other hand, in case # 7, we succeeded in making osimertinib resistant in about 100 days and established a PDX model of osimertinib resistance. From the above results, it was possible to establish the PDX model system, which was the original purpose, and to apply the PDX model to the therapeutic effect determination of EGFR inhibitors.

Academic Significance and Societal Importance of the Research Achievements

前臨床モデルであるヒトがん細胞株を用いた研究においては、患者の腫瘍が本来有している腫瘍組織微小環境や腫瘍不均一性が欠如しており、実臨床との薬剤感受性の乖離がしばしば問題となる。しかし、本研究で作製に成功したPDXモデルでは患者組織を反映しており、治療薬のスクリーニング、薬剤耐性研究に活用できる。さらに、PDXモデルを利用し解析することにより、肺がんの再発あるいはEGFR阻害薬耐性となった患者に新たな治療薬を提案でき、肺がん患者の予後改善につながることが期待され、本研究成果は社会的に意義がある。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (2 results)

All 2020 2019

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results)

  • [Journal Article] Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer2020

    • Author(s)
      Wang Rong、Yamada Tadaaki、Kita Kenji、Taniguchi Hirokazu、Arai Sachiko、Fukuda Koji、Terashima Minoru、Ishimura Akihiko、Nishiyama Akihiro、Tanimoto Azusa、Takeuchi Shinji、Ohtsubo Koshiro、Wang Wei、Suzuki Takeshi、Yano Seiji et. al.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 4607-4607

    • DOI

      10.1038/s41467-020-18442-4

    • NAID

      120007186801

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Patient‐derived xenograft models of non‐small cell lung cancer for evaluating targeted drug sensitivity and resistance2019

    • Author(s)
      Kenji Kita, Koji Fukuda, Hiro Takahashi, Azusa Tanimoto, Akihiro Nishiyama, Sachiko Arai, Shinji Takeuchi, Kaname Yamashita, Koshiro Ohtsubo, Sakiko Otani, Naohiro Yanagimura, Chiaki Suzuki, Hiroko Ikeda, Masaya Tamura, Isao Matsumoto, Seiji Yano
    • Journal Title

      Cancer Science

      Volume: 110(10) Issue: 10 Pages: 3215-3224

    • DOI

      10.1111/cas.14171

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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