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

Highlights ABCB1 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.

Automated summary

Overexpression of ABCBC1 significantly reduces sensitivity to OTS964 in cells and tumors, which can be antagonized by verapamil. OTS964 also induces resistance to other ABCBC1 substrate-drugs by stimulating ATPase activity and upregulating ABCBC1 expression levels, with comparable affinity to the substrate-binding site of human ABCBC1 protein.