Development of Novel Therapeutic Agents Targeting Regulatory Mechanisms of Cell Membrane Morphology for HER2-positive breast cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18029
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Ehime University
• Principal Investigator: Murakami Akari 愛媛大学, 医学部附属病院, 助教(病院教員) (60722593)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: HER2陽性乳癌 / 細胞膜 / Rac1 / アルファスクリーン / タンパク質間相互作用

Outline of Final Research Achievements

Although the HER2-targeted therapy is the first-line and effective therapy towards HER2-positive breast cancers, the development of drug resistance has been problematic. In addition, all the current anti-cancer drugs for HER2-positive breast cancer inhibit HER2. We have recently found that the ubiquitin E3 complex CUL3/KCTD10 is essential for cell growth through the constitutive degradation of RhoB specifically in HER2-positive breast cancer cells. In this study, we identified a RhoB-interacting protein which is essential for EGF-induced membrane ruffle formation as well as cell proliferation of HER2-positive breast cancer cells. By utilizing AlphaScreen, we also identified a couple of compounds which inhibit the CUL3/KCTD10 interaction leading to the inhibition of HER2-positive breast cancer cell growth

Free Research Field

腫瘍生物学、乳腺外科学

Academic Significance and Societal Importance of the Research Achievements

現行のHER2陽性乳癌に対する治療薬は、薬剤耐性の問題から、投与期間は限定的である。本研究ではHER2以外の分子基盤を創薬標的としているので、本研究を通して導出されたシーズ化合物は、抗HER2療法と併用して使用可能な新たなHER2陽性乳癌治療薬として、今後の開発が期待される。