Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers
文献类型：期刊论文
| 作者 | Li, Yongpeng2,3; Li, Lin3,4; Fu, Haoyu3; Yao, Qing3; Wang, Lei1,3; Lou, Liguang1,2,3,4
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| 刊名 | AMERICAN JOURNAL OF CANCER RESEARCH
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| 出版日期 | 2023 |
| 卷号 | 13期号:1页码:161-+ |
| ISSN号 | 2156-6976 |
| 关键词 | Antibody-drug conjugate DS-8201 PARP ATR synergy DNA damage |
| 通讯作者 | Wang, Lei(wanglei@simm.ac.cn) ; Lou, Liguang(lglou@simm.ac.cn) |
| 英文摘要 | The therapeutic management of various HER2-positive malignancies involves the use of HER2-targeted antibody-drug conjugates (ADCs). The primary mechanism of action of ADCs is the release of cytotoxic chemicals, which leads to single-or double-strand DNA breaks and cell death. Since both endogenous and exogenous sources of DNA damage are unavoidable, cells have evolved DNA damage-repair mechanisms. Therefore, combining inhibi-tors of DNA damage repair and HER2-targeted ADCs may be a practical strategy for treating HER2-positive cancers. Effects of the HER2-targeted ADC, DS-8201, in combination with PARPi (AZD2281), a DNA damage repair inhibi-tor that targets poly(ADP-ribose) polymerase, and ATRi (BAY1895344), which inhibits the serine/threonine kinase ATR, were determined by assessing cell-growth inhibition, apoptosis and cell-cycle arrest, as well as using in vivo pharmacodynamic studies. Combined use of AZD2281 and BAY1895344 synergistically potentiated the inhibitory effects of DS-8201 on the growth of HER2-positive cancer cells, inducing DNA damage and apoptosis, but had no effect on HER2-negative MDA-MB-231 breast cancer cells. Our data demonstrate that DS-8201 and DNA damage repair inhibitors together have synergistic anticancer effects in NCI-N87 xenograft models, effects that may reflect upregulation of gamma-H2AX protein in tumor tissues. Collectively, our results indicate that the combination of DS-8201, BAY1895344, and AZD2281 exerts significant synergistic antitumor activity, suggesting that DNA damage-repair inhibitors in combination with HER2-targeted ADCs is a potential approach for treating HER2-positive malignancies, offering a promising strategy for future clinical applications. |
| WOS关键词 | DNA-DAMAGE REPAIR ; BREAST-CANCER ; TRASTUZUMAB DERUXTECAN ; COMBINATION ; POLY(ADP-RIBOSE) ; BIOMARKER ; SAFETY |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[18DZ2293200] ; Yunnan Province Sciences and Technology Plan[202102AA310026] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| 出版者 | E-CENTURY PUBLISHING CORP |
| WOS记录号 | WOS:000950570900009 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306529]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Lei; Lou, Liguang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Media, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Media, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Media, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Yongpeng,Li, Lin,Fu, Haoyu,et al. Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers[J]. AMERICAN JOURNAL OF CANCER RESEARCH,2023,13(1):161-+. |
| APA | Li, Yongpeng,Li, Lin,Fu, Haoyu,Yao, Qing,Wang, Lei,&Lou, Liguang.(2023).Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers.AMERICAN JOURNAL OF CANCER RESEARCH,13(1),161-+. |
| MLA | Li, Yongpeng,et al."Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers".AMERICAN JOURNAL OF CANCER RESEARCH 13.1(2023):161-+. |
入库方式： OAI收割
来源：上海药物研究所
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