Research for detecting and overcoming multidrug resistance caused by EGFR-C797S/T790M mutation

• Project/Area Number: 18K15936
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: UCHIBORI Ken 公益財団法人がん研究会, 有明病院 呼吸器内科, 医長 (40633053)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: EGFR遺伝子変異 / EGFR阻害剤 / Osimertinib / C797S変異 / 薬剤耐性 / EGFR / EGFR-TKI / C797S / 血漿cfDNA / EGFR遺伝子 / 耐性 / チロシンキナーゼ阻害剤

Outline of Final Research Achievements

We investigated a highly sensitive method for detecting EGFR mutations in plasma cfDNA using droplet digital PCR, and confirmed the appearance of T790M/C797S in some patients who developed resistance to osimertinib treatment after T790M. Moreover, we found that our ddPCR system is expected to be a method for recognizing signs of drug resistance earlier than imaging.
In December 2020, a multi-center Phase I/II study of brigatinib plus panitumumab combination therapy for C797S-resistant mutation-positive advanced EGFR lung cancer (AMED Innovative Cancer Research) started and is now underway. We believe that the above findings will be of great benefit to the applicant in our role as an investigator.

Academic Significance and Societal Importance of the Research Achievements

EGFR阻害剤による肺癌治療は、患者ごとの最適化治療が急速に進歩しているとともに、耐性出現後の克服法の重要性が非常に大きくなっている。現在EGFR阻害剤として最も重要視されるのはosimerinibであるが、本研究によりosimertinib耐性を生じるC797S変異を血漿から検出可能であることを検出でき、CTなどによる標準的な効果判定よりも早期に耐性を予見できたことは大きな意味を持つ。すなわち、osimertinib後の治療開発を進めるにあたり、対象となる症例を簡便かつ正確に抽出できる手法の確立に貢献すると期待される。

Research Products

• [Journal Article] Monitoring epidermal growth factor receptor C797S mutation in Japanese non?small cell lung cancer patients with serial cell‐free DNA evaluation using digital droplet PCR (2021)
  • Author(s): Ariyasu Ryo、Uchibori Ken、Sasaki Takaaki、Tsukahara Mika、Kiyotani Kazuma、Yoshida Ryohei、Ono Yusuke、Kitazono Satoru、Ninomiya Hironori、Ishikawa Yuichi、Mizukami Yusuke、Yanagitani Noriko、Fujita Naoya、Nishio Makoto、Katayama Ryohei
  • Journal Title: Cancer Science Volume: - Issue: 6 Pages: 2371-2380
  • DOI: 10.1111/cas.14879
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity (2021)
  • Author(s): Yoshizawa Takahiro、Uchibori Ken、Araki Mitsugu、Matsumoto Shigeyuki、Ma Biao、Kanada Ryo、Seto Yosuke、Oh-hara Tomoko、Koike Sumie、Ariyasu Ryo、Kitazono Satoru、Ninomiya Hironori、Takeuchi Kengo、Yanagitani Noriko、Takagi Satoshi、Kishi Kazuma、Fujita Naoya、Okuno Yasushi、Nishio Makoto、Katayama Ryohei
  • Journal Title: npj Precision Oncology Volume: 5 Issue: 1 Pages: 32-32
  • DOI: 10.1038/s41698-021-00170-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 初回Osimertinib開始前の血漿中TP53変異はnegative biomarkerの可能性がある (2020)
  • Author(s): 内堀健、小楠真典 、次富亮輔 、眞鍋亮、坂本博昭、戸塚猛大、吉田寛、網野喜彬、有安亮、北園聡、栁谷典子、宝来威、片山量平、林理絵、Siew-Kee Low、西尾誠人
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] EGFR変異陽性肺癌における血中EGFR変異の経時的変化 (2019)
  • Author(s): 内堀 健
  • Organizer: 第23回日本がん分子標的治療学会学術集会
• [Presentation] 初回Osimertinib治療中におけるNGSを用いた血漿cell free DNAの経時的解析 (2019)
  • Author(s): 内堀 健
  • Organizer: 第60回日本肺癌学会学術集会