HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade
文献类型：期刊论文
| 作者 | Li, Wen-jing2,3; Kang, Kai-ge2,3; Zhang, Yu-xiang2,3; Zhao, Xin-xin1; Zhu, Xi3; Tang, Jiao3; Li, Yong-peng3; Fu, Hao-yu3; Yao, Qing3; Wang, Lei3 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2025-09-10 |
| 页码 | 12 |
| 关键词 | HER2-positive tumors DS-8201 DNA damage response FoxO1 HER3 upregulation ATR inhibitor |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-025-01647-y |
| 通讯作者 | Wang, Lei(wanglei@simm.ac.cn) ; Lou, Li-guang(lglou@simm.ac.cn) |
| 英文摘要 | The anti-HER2 antibody-drug conjugate (ADC) DS-8201 presents new hope for patients with advanced HER2-positive tumors. Its clinical application, however, is hindered by serious adverse reactions and reduced efficacy following long-term treatment. In this study, we investigated the factors influencing the sensitivity of DS-8201 and developed effective combination regimens to optimize its therapeutic efficacy. We showed that HER3 upregulation diminished the sensitivity of HER2-positive tumor cells to DS-8201. We found that DS-8201 treatment activated DNA damage repair responses in BT-474 cells, in which the ATR kinase pathway induced the expression of the HER3 transcription factor FoxO1, leading to increased HER3 levels. This process was triggered by the payload component of DS-8201, the topoisomerase I inhibitor DXd, rather than the antibody. Based on this finding, we showed that combining DS-8201 with either a HER3-targeting antibody (SIBP-03) or an ATR inhibitor (BAY1895344) resulted in significant synergistic antitumor efficacy without substantial toxicity in vitro or in vivo. Overall, this study revealed that the ATR/FoxO1/HER3 pathway plays a critical role in modulating the efficacy of DS-8201, suggesting that combining DS-8201 with ATR or HER3 inhibition represents a promising therapeutic strategy for HER2-positive cancers. |
| WOS关键词 | ANTIBODY-DRUG CONJUGATE ; TRASTUZUMAB DERUXTECAN ; PATRITUMAB DERUXTECAN ; BREAST-CANCER ; FAMILY ; PHARMACOKINETICS ; ACTINOMYCIN ; ACTIVATION ; OVARIAN ; SAFETY |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[18DZ2293200] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001567723000001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321423]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Lei; Lou, Li-guang |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Wen-jing,Kang, Kai-ge,Zhang, Yu-xiang,et al. HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade[J]. ACTA PHARMACOLOGICA SINICA,2025:12. |
| APA | Li, Wen-jing.,Kang, Kai-ge.,Zhang, Yu-xiang.,Zhao, Xin-xin.,Zhu, Xi.,...&Lou, Li-guang.(2025).HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade.ACTA PHARMACOLOGICA SINICA,12. |
| MLA | Li, Wen-jing,et al."HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade".ACTA PHARMACOLOGICA SINICA (2025):12. |
入库方式： OAI收割
来源：上海药物研究所
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