Development of new protein-knockdown compounds possessing tumor-inhibitory activity

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K05856
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: Atsumi Sonoko 公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (30260136)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: EGFRｖIII / EFDR-ADC / Ertredin

Outline of Final Research Achievements

Ertredin was expected to be a protein modulator because of the results in the mouse cells. We investigated the effect of Ertredin on EGFRvIII, an oncoprotein, transfected to human glioblastoma cells. EGFRvIII was decreased after addition of Ertredin in brief time, but ubiquitination of the related protein was not seen. Therefore, Ertredin seemed not having protein modulator activity. On the other hand, Ertredin induced serine phosphorylation and endocytosis of EGFRvIII and EGFRwt （non-canonical endocytosis） in the human glioblastoma cells. In glioblastoma cells transfected with EGFRvIII, 7MeErtredin, a relative of Ertredin, having higher inducible activity of non-canonical endocytosis, promoted the antibody drug complex targeting EGFR (EGFR-ADC) activity.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

HER（ヒト上皮成長因子受容体）を過剰発現したがんを標的としてHER2のADCが開発、承認されている。一方、EGFR（HER1）はEGFとの結合後細胞内に取り込まれるが（定型的飲作用）、抗体結合がこれを抑制しADCが細胞内に取り込まれないことが課題である。今回Ertredinおよび7MeErtredinがEGFRvIIIおよびEGFRwtの非定型的飲作用を誘導すし、EGFRvIII発現脳腫瘍においてEGFR―ADC活性を促進することを明らかにした。非定型的飲作用がEGFR―ADCの細胞内取り込みを誘導し、その活性促進に利用でき、今後のがん治療への応用が期待されることを示した。