Development of new therapeutic strategy based on gene expression and mutation profiles in EGFR mutant lung cancer

• Project/Area Number: 16H05431
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Okayama University
• Principal Investigator: Toyooka Shinichi 岡山大学, 医歯薬学総合研究科, 教授 (30397880)
• Co-Investigator(Kenkyū-buntansha): 三好 新一郎 岡山大学, 医歯薬学総合研究科, 特命教授 (00190827) ; 冨田 秀太 岡山大学, 医歯薬学総合研究科, 准教授 (10372111) ; 枝園 和彦 岡山大学, 大学病院, 助教 (30708079) ; 山本 寛斉 岡山大学, 大学病院, 助教 (40467733) ; 阪口 政清 岡山大学, 医歯薬学総合研究科, 教授 (70379840) ; 宗 淳一 岡山大学, 大学病院, 講師 (90559890)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2016: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 肺癌 / 分子標的薬 / 分子バーコード / 次世代シークエンサー / 薬剤耐性 / EMT / PDX / 非小細胞肺癌 / 分子標的治療薬 / EGFR / 次世代シーケンサー / 癌 / 外科

Outline of Final Research Achievements

We performed the research to develop new therapeutic strategy in EGFR mutant non-small cell lung cancer; prediction about an acquired resistance mechanism to EGFR-TKI and selecting a preventative therapy against emergence of resistance. Targeted deep sequencing with the molecular barcoding system showed a high incidence of coexistence of EGFR common driver mutations and uncommon mutations. In cellular models, AXL was often upregulated in EMT mediated osimertinib resistant cell lines, and addition of cabozantinib, an AXL inhibitor, restored the sensitivity to osimertinib. Drug repositioning analysis revealed that monensin have an preventive effect against EMT, and also EMT-mediated acquired resistance.

Academic Significance and Societal Importance of the Research Achievements

肺癌治療は、分子標的治療の導入により大いに前進したが、一方で現時点では耐性化は不可避でありこれを防ぐ手立てはない。本研究の成果は、治療前から出現する可能性のある耐性機構を予測し、耐性化を阻止する「先制治療」の確立につながる重要な知見である。特にEGFR-TKIのみならず各種抗癌剤に対する耐性機構としても重要なEMT化の阻止は、肺癌薬物治療全体に大きなインパクトを及ぼすことが期待される。そのため、本研究は全肺癌治療成績の大幅な改善に繋がると考えられる。

Research Products

• [Journal Article] Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naive lung adenocarcinoma (2019)
  • Author(s): Namba Kei、Tomida Shuta、Matsubara Takehiro、Takahashi Yuta、Kurihara Eisuke、Ogoshi Yusuke、Yoshioka Takahiro、Takeda Tatsuaki、Torigoe Hidejiro、Sato Hiroki、Shien Kazuhiko、Yamamoto Hiromasa、Soh Junichi、Tsukuda Kazunori、Toyooka Shinichi
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s12885-019-5374-1
  • Peer Reviewed / Open Access
• [Journal Article] Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells (2019)
  • Author(s): Namba Kei、Shien Kazuhiko、Takahashi Yuta、Torigoe Hidejiro、Sato Hiroki、Yoshioka Takahiro、Takeda Tatsuaki、Kurihara Eisuke、Ogoshi Yusuke、Yamamoto Hiromasa、Soh Junichi、Tomida Shuta、Toyooka Shinichi
  • Journal Title: Molecular Cancer Research Volume: 17 Issue: 2 Pages: 499-507
  • DOI: 10.1158/1541-7786.mcr-18-0628
  • Peer Reviewed
• [Presentation] Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells (2019)
  • Author(s): Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hiroki Sato, Takahiro Yoshioka, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Detection of multiple low-frequency mutations by molecular-barcode sequencing (2017)
  • Author(s): Kei Namba, Shuta Tomida, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Multiple acquired resistance mechanisms against third generation EGFR-TKI osimertinib in non-small cell lung cancer cells (2017)
  • Author(s): Kei Namba, Kazuhiko Shien, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka
  • Organizer: 第58回日本肺癌学会学術集会
• [Presentation] Detection of multiple low-frequency mutations by molecular-barcode sequencing (2016)
  • Author(s): Kei Namba, Shuta Tomida, Kazuhiko Shien, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
  • Organizer: 第57回日本肺癌学会総会
  • Place of Presentation: 福岡市
  • Year and Date: 2016-12-19
• [Presentation] Detection of multiple low-frequency mutations by molecular-barcode sequencing (2016)
  • Author(s): Kei Namba, Shuta Tomida, Ken Suzawa, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
  • Organizer: IASLC 17TH WORLD CONFERENCE ON LUNG CANCER
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-12-04
  • Int'l Joint Research