Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression
文献类型：期刊论文
| 作者 | Wang, Xiaobo1; Huang, Jing2,3; Liu, Fenglin4; Yu, Qian1; Wang, Ruina1; Wang, Jiaqi1; Zhu, Zewen1; Yu, Juan5; Hou, Jun5; Shim, Joong Sup6,7 |
| 刊名 | JOURNAL OF CLINICAL INVESTIGATION
 |
| 出版日期 | 2023-05-01 |
| 卷号 | 133期号:9页码:12 |
| ISSN号 | 0021-9738 |
| DOI | 10.1172/JCI161929 |
| 通讯作者 | Jiang, Wei(jiangw@fudan.edu.cn) ; Li, Zengxia(lizengxia@fudan.edu.cn) ; Zhang, Yuanyuan(zhangyy@simm.ac.cn) ; Dang, Yongjun(yjdang@cqmu.edu.cn) |
| 英文摘要 | Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-KB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors. |
| WOS关键词 | ACQUIRED-RESISTANCE ; BLOCKADE ; PHOSPHORYLATION ; ALISERTIB ; PATHWAY |
| 资助项目 | National Natural Science Foundation of China[22137002] ; National Natural Science Foundation of China[21877016] ; National Natural Science Foundation of China[81820108030] ; National Natural Science Foundation of China[81772962] ; National Natural Science Foundation of China[92253305] ; National Natural Science Foundation of China[82273021] ; National Natural Science Foundation of China[81972621] ; National Natural Science Foundation of China[82273946] ; National Natural Science Foundation of China[81803554] ; National Key Research and Development Program of China[2022YFC2804800] ; Open Project of the State Key Laboratory of Respiratory Diseases[SKLRD-OP-202213] ; University Innovation Research Group in Chongqing[CXQT21016] ; Chongqing Talent Program Project[CQYC20200302119] ; High-Level Innovation Platform Cultivation Plan of Chongqing ; Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| 出版者 | AMER SOC CLINICAL INVESTIGATION INC |
| WOS记录号 | WOS:000996388600002 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306623]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Wei; Li, Zengxia; Zhang, Yuanyuan; Dang, Yongjun |
| 作者单位 | 1.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res, Shanghai, Peoples R China 3.China Univ Chinese Acad Sci, Beijing, Peoples R China 4.Fudan Univ, Zhongshan Hosp, Dept Gen Surg, Shanghai, Peoples R China 5.Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China 6.Univ Macau, Fac Hlth Sci, Dept Pharmaceut Sci, Taipa, Macao, Peoples R China 7.Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macao, Peoples R China 8.Chongqing Med Univ, Affiliated Hosp 2, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing, Peoples R China 9.Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, 1 Yixueyuan Rd Bldg Lib,8th Floor, Chongqing 400016, Peoples R China 10.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Xiaobo,Huang, Jing,Liu, Fenglin,et al. Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression[J]. JOURNAL OF CLINICAL INVESTIGATION,2023,133(9):12. |
| APA | Wang, Xiaobo.,Huang, Jing.,Liu, Fenglin.,Yu, Qian.,Wang, Ruina.,...&Dang, Yongjun.(2023).Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.JOURNAL OF CLINICAL INVESTIGATION,133(9),12. |
| MLA | Wang, Xiaobo,et al."Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression".JOURNAL OF CLINICAL INVESTIGATION 133.9(2023):12. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。