PBK/TOPK inhibitor OTS964 resistance is mediated by ABCB1-dependent transport function in cancer: in vitro and in vivo study

Molecular Cancer

Zhe-Sheng Chen¹  Qiu-Xu Teng¹  Jing-Quan Wang¹  Zhuo-Xun Wu¹  Yuqi Yang¹  Zi-Ning Lei²  Ning Ji³  Sabrina Lusvarghi⁴  Suresh V. Ambudkar⁴ 

[1] Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, 11439, New York City, NY, USA;Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, 11439, New York City, NY, USA;Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China;Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, 11439, New York City, NY, USA;Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China;Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, 20892, Bethesda, USA;

关键词: T-LAK cell-originated protein kinase (TOPK);    PDZ-binding kinase (PBK);    OTS964;    ATP-binding cassette sub-family B member 1 (ABCB1);    Multidrug resistance (MDR);   

DOI  :  10.1186/s12943-022-01512-0

来源: Springer

【 摘 要 】

tsABCB1 overexpression significantly desensitized both drug-selected and gene-transfected cells, which overexpress ABCB1, to OTS964 and that this drug resistance can be antagonized by verapamil, a known ABCB1 inhibitor. Consistently, a similar trend was observed in tumor-bearing mice.OTS964 stimulated ATPase activity of ABCB1 and upregulated expression levels of ABCB1, resulting in induced resistance to other ABCB1 substrate-drugs, such as paclitaxel.OTS964 received a comparable affinity score and can dock into the substrate-binding site of human ABCB1 protein.

【 授权许可】

CC BY