Novel therapeutic method for HER2 active cancer focusing on HER2 novel binding molecule cytokeratin 19

• Project/Area Number: 16K10681
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Okayama University
• Principal Investigator: SOH JUNICHI 岡山大学, 大学病院, 講師 (90559890)
• 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) ; 佃 和憲 岡山大学, 大学病院, 講師 (20346430) ; 豊岡 伸一 岡山大学, 医歯薬学総合研究科, 教授 (30397880) ; 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) ; 浅野 博昭 岡山大学, 大学病院, 助教 (70534775)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: HER2 / サイトケラチン19 / ERBB2

Outline of Final Research Achievements

The HER2 protein is activated in lung cancer, gastric cancer, and breast cancer. Although HER2 gene mutation / amplification is observed in lung cancer, HER2 gene amplification in particular is noted as a factor contributing to acquired resistance of EGFR tyrosine kinase inhibitors. Existing HER2 molecule-targeted drugs have problems with efficacy and drug resistance, and new therapeutic strategies for HER2-active tumors are needed. We identified a novel molecule cytokeratin 19 (one of the intermediate filaments of the cytoskeleton) involved in HER2 protein activation. Furthermore, we reported the therapeutic effect (in vitro & vivo) of HER2 molecule targeting drug (Afatinib) on gastric cancer cell lines. We used it exploratoryly in HER2 mutation positive cancer patients without Afatinib indication and reported its therapeutic effect. The therapeutic effect (in vitro & vivo) of pan-HER inhibitor Neratinib in HER2-activated lung cancer cell line was also reported.

Academic Significance and Societal Importance of the Research Achievements

今回の検討は、HER2活性型腫瘍における病態の解明の一助となると同時に、新規HER2標的薬の治療効果を基礎的に検討した。また、HER2阻害薬の適応を持たない腫瘍において、実臨床においてその治療効果を検証し、その有用性を示すことができた。現在、遺伝子プロファイルに基づく治療戦略が脚光を浴びているが、本研究のアプローチはまさに体現するものであり、社会的意義は大きいと考える。今後、同様のアプローチにより、多くの知見を積まれ、がん治療の治療成績がさらに改善することを期待する。

Research Products

• [Journal Article] Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations. (2019)
  • Author(s): Ogoshi Y, Shien K, Yoshioka T, Torigoe H, Sato H, Sakaguchi M, Tomida S, Namba K, Kurihara E, Takahashi Y, Suzawa K, Yamamoto H, Soh J, Toyooka S
  • Journal Title: Oncol Lett. Volume: - Pages: 2729-2736
  • DOI: 10.3892/ol.2019.9908
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer. (2018)
  • Author(s): Yoshioka T, Shien K, Namba K, Torigoe H, Sato H, Tomida S, Yamamoto H, Asano H, Soh J, Tsukuda K, Nagasaka T, Fujiwara T, Toyooka S.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 4 Pages: 1166-1176
  • DOI: 10.1111/cas.13546
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E. (2018)
  • Author(s): Yamamoto H, Toyooka S, Ninomiya T, Matsumoto S, Kanai M, Tomida S, Kiura K, Muto M, Suzawa K, Desmeules P, Kris MG, Li BT, Ladanyi M.
  • Journal Title: Oncologist Volume: 23 Issue: 2 Pages: 150-154
  • DOI: 10.1634/theoncologist.2017-0345
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. (2016)
  • Author(s): Ohtsuka T, Sakaguchi M, Yamamoto H, Tomida S, Takata K, Shien K, Hashida S, Miyata-Takata T, Watanabe M, Suzawa K, Soh J, Youyi C, Sato H, Namba K, Torigoe H, Tsukuda K, Yoshino T, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 39557-39557
  • DOI: 10.1038/srep39557
  • Peer Reviewed / Open Access
• [Presentation] Antitumor effect of neratinib in lung cancers harboring HER2 oncogene alterations (2018)
  • Author(s): Yusuke Ogoshi, shinichi Toyooka, Jyunichi Soh, hiromasa Yamamoto, Kazuhiko Shien, Hidejiro torigoe, Hiroki sato, Takahiro Yoshioka, Kei Namba, Yuta Takahashi, and Eisuke Kurihara
  • Organizer: AACR2018
  • Int'l Joint Research