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

• Project/Area Number: 18K08141
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kanazawa 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: ¥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)
• Keywords: PDX / 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。

Research Products

• [Journal Article] Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer (2020)
  • 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
  • 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 resistance (2019)
  • 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
  • Peer Reviewed / Open Access