A study of molecular biology and liquid biopsy for non-small cell lung cancer positive for HER2 mutations

• Project/Area Number: 18K15214
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyushu University
• Principal Investigator: Iwama Eiji 九州大学, 大学病院, 助教 (40567343)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: HER2 / 抗体薬物複合体 / リキッドバイオプシー / HER2遺伝子変異 / ダイマー / 分子標的治療薬 / 遺伝子変異 / ダイマー形成

Outline of Final Research Achievements

Trastuzumab emtansine, antibody-drug conjugate, was effective for EGFR mutated-cancer cell lines even though the expression of HER2 was low in the cell lines. Homodimer of HER2-HER2 was localized at the cell surface and heterodimers of HER2-EGFR or HER2-HER3 were located within cells, indicating that HER2 was internalized into cytoplasm via HER2-EGFR heterodimer in EGFR-mutated cell lines. Presence or increase or disappearance of the EGFR activating mutations in plasma was prognostic factors for EGFR-TKI treatment.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、HER2を標的とした分子標的治療薬がHER2高発現の腫瘍以外にも効果を有することが明らかとなり、更なる研究によって治療選択肢の拡大につながる可能性がある。現在、新規研究として「EGFR遺伝子変異陽性肺癌における抗体薬物複合体の作用機序に関する研究」を推進中である。2021年3月ゲノム医療の一環として次世代シークエンサーを用いたリキッドバイオプシー検査が承認され、今後リキッドバイオプシーが日常臨床で使用されるようになる。このような背景において、本研究で示した分子標的治療薬の予後予測におけるリキッドバイオプシーの有用性は重要な意義を有する。

Research Products

• [Journal Article] Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor-tyrosine kinase inhibitors. (2020)
  • Author(s): Iwama E, Sakai K, Hidaka N, Inoue K, Fujii A, Nakagaki N, Ota K, Toyozawa R, Azuma K, Nakatomi K, Harada T, Hisasue J, Sakata S, Shimose T, Kishimoto J, Nakanishi Y, Nishio K, Okamoto I.
  • Journal Title: Cancer Volume: 126(1) Issue: 1 Pages: 219-227
  • DOI: 10.1002/cncr.32481
  • Peer Reviewed
• [Journal Article] Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors. (2019)
  • Author(s): Yonesaka K, Iwama E, Hayashi H, Suzuki S, Kato R, Watanabe S, Takahama T, Tanizaki J, Tanaka K, Takeda M, Sakai K, Azuma K, Chiba Y, Atagi S, Nishio K, Okamoto I, Nakagawa K.
  • Journal Title: Ｓｃｉｅｎｔｉｆｉｃ rｅｐｏｒｔｓ Volume: 9(1) Issue: 1 Pages: 19501-19501
  • DOI: 10.1038/s41598-019-55939-5
  • Peer Reviewed
• [Journal Article] Genetic Profiling of Non‐Small Cell Lung Cancer at Development of Resistance to First‐ or Second‐Generation EGFR‐TKIs by CAPP‐Seq Analysis of Circulating Tumor DNA (2019)
  • Author(s): Otsubo Kohei、Sakai Kazuko、Takeshita Masafumi、Harada Daijiro、Azuma Koichi、Ota Keiichi、Akamatsu Hiroaki、Goto Koichi、Horiike Atsushi、Kurata Takayasu、Nakagaki Noriaki、Nosaki Kaname、Iwama Eiji、Nakanishi Yoichi、Nishio Kazuto、Okamoto Isamu
  • Journal Title: The Oncologist Volume: 24 Issue: 8 Pages: 1022-1026
  • DOI: 10.1634/theoncologist.2019-0101
  • Peer Reviewed / Open Access
• [Journal Article] Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing. (2018)
  • Author(s): Iwama E, Sakai K, Azuma K, Harada D, Nosaki K, Hotta K, Nishio M, Kurata T, Fukuhara T, Akamatsu H, Goto K, Shimose T, Kishimoto J, Nakanishi Y, Nishio K, Okamoto I.
  • Journal Title: Cancer Sci Volume: 109 Issue: 12 Pages: 3921-3933
  • DOI: 10.1111/cas.13820
  • Peer Reviewed / Open Access
• [Presentation] EGFR遺伝子変異陽性肺癌治療における大規模前向きリキッドバイオプシー研究 (2019)
  • Author(s): 岩間映二
  • Organizer: 第116 回日本内科学会講演会