Development of Novel Therapeutic Agents Targeting Regulatory Mechanisms of Cell Membrane Morphology for HER2-positive breast cancer
| Project/Area Number |
19K18029
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 55010:General surgery and pediatric surgery-related
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| Research Institution | Ehime University |
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Principal Investigator |
Murakami Akari 愛媛大学, 医学部附属病院, 助教(病院教員) (60722593)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| 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 / CUL3 / 細胞膜形態変化 |
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| Outline of Research at the Start |
HER2陽性乳癌は乳癌全体の約20%を占め、高い増殖能と転移能を有し予後不良である。HER2の機能を阻害する抗HER2医薬品はHER2陽性乳癌に著効するが耐性化が臨床上重大な問題となっている。そこで、本研究ではHER2陽性乳癌細胞の細胞膜形態制御機構を標的としたHER2陽性乳癌に対する新規分子標的薬のシーズ化合物の導出を狙う。具体的には申請者が最近発見したHER2陽性乳癌細胞の細胞膜形態制御機構に必須なユビキチンE3複合体の形成阻害剤をアルファスクリーンシステムにより探索する。同時に当該タンパク質複合体のヒトHER2陽性乳癌組織における発現と予後との相関を解析し、臨床的重要性を導出する。
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| 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
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| 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。
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Report
(4 results)
Research Products
(4 results)
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[Presentation] A novel mechanism of phosphatase activation for EGFR by Cullin-3/KCTD10 ubiquitin E3 complex in HER-2-positive breast cancer cells.2021
Author(s)
Ⅴ-1)Nishiyama K, Maekawa M, Murakami A, Utsunomiya K, Takemoto K, Kusakabe E, Noda H, Aoki R, Taguchi K, Yamashita M, Nakagita T, Nakayama J, Chosei M, Kiyoi T, Kamei Y, Takeda H, Takada Y, Higashiyama S
Organizer
The 2021 San Antonio Breast Cancer Symposium
Related Report
Int'l Joint Research
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