BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair
文献类型：期刊论文
| 作者 | Chi, Shuaishuai3,4; Wei, Fan4; Li, Yangsha2,4; Yu, Lei2,4; Ma, Chuyao2,4; Fang, Yanfen1,2,4; Yang, Biyu4; Chen, Yi1,2,4 ; Ding, Jian1,2,3
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| 刊名 | TRANSLATIONAL ONCOLOGY
 |
| 出版日期 | 2025 |
| 卷号 | 51页码:11 |
| 关键词 | CDK4 BRD4 Breast cancer Protein stability DNA damage |
| ISSN号 | 1936-5233 |
| DOI | 10.1016/j.tranon.2024.102212 |
| 通讯作者 | Wei, Fan(weifan3@simm.ac.cn) ; Chen, Yi(ychen@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) |
| 英文摘要 | CDK4/6 inhibitors have shown clinical benefits in hormone receptor positive breast cancer. However, monotonous indications and unclear resistance mechanisms greatly limit the clinical application of these inhibitors. We attempt to improve the therapeutic effect of CDK4/6 inhibitors against breast cancer by combination with BET inhibitors. Although this combination therapy has begun to be studied in recent clinical trials, the mechanism of action is not clear. We provide the evidence that CDK4/6 inhibitor LY2835219 plus BRD4 inhibitor OTX-015 synergistically inhibits both ER positive and triple-negative breast cancer cells growth in vitro and in vivo. Mechanistically, LY2835219 accelerates the degradation of BRD4 through the proteasome pathway via inhibition of CDK4 activity. This instability of BRD4 protein in turn enhances the anti-tumor effect of CDK4/6 inhibitor by suppressing transcription of DNA damage repair gene RAD51, and synergistically promotes gamma-H2AX accumulation and DNA double-strand breaks. Overall, we demonstrated the potential combined therapeutic value of CDK4/6 and BRD4 inhibitors and elucidated the mechanisms, which may provide a new rational approach for breast cancer patients. |
| WOS关键词 | GENE-EXPRESSION ; CELL-LINES ; TRANSCRIPTION ; OVEREXPRESSION ; COMBINATION ; DISRUPTION ; PROGNOSIS ; SUBTYPES ; OTX015 ; TUMORS |
| 资助项目 | Program of Shanghai Ac-ademic Research Leader[22XD1404400] ; Shandong Laboratory Pro-gram[SYS202205] ; Science and Technology Commission of Shanghai Municipality[21140902000] ; National Natural Sciences foun-dation of China[82373891] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:001366617200001 |
| 出版者 | ELSEVIER SCIENCE INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314807]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wei, Fan; Chen, Yi; Ding, Jian |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Zhejiang Univ, Sch Med, Dept Basic Med Sci, Hangzhou 310058, Zhejiang, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chi, Shuaishuai,Wei, Fan,Li, Yangsha,et al. BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair[J]. TRANSLATIONAL ONCOLOGY,2025,51:11. |
| APA | Chi, Shuaishuai.,Wei, Fan.,Li, Yangsha.,Yu, Lei.,Ma, Chuyao.,...&Ding, Jian.(2025).BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair.TRANSLATIONAL ONCOLOGY,51,11. |
| MLA | Chi, Shuaishuai,et al."BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair".TRANSLATIONAL ONCOLOGY 51(2025):11. |
入库方式： OAI收割
来源：上海药物研究所
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