OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance.

Yuqi Yang,Zhuo-Xun Wu,Sabrina Lusvarghi,Qiu-Xu Teng,Jing-Quan Wang,Suresh V Ambudkar,Zi-Ning Lei,Dong-Hua Yang,Zhe-Sheng Chen

doi:10.3389/fphar.2021.620874

Abstract

OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.

Highlights

T-LAK cell-originated protein kinase (TOPK) is a mitogen-activated protein kinase-like kinase (MAPKK), which plays a critical role in facilitating cell cycle control and mitotic progression (Herbert et al, 2018)
An MTT assay was performed to examine the susceptibility of OTS964 to multidrug resistance (MDR) mediated by ATPbinding cassette sub-family G member 2 (ABCG2)
This is because Robey et al showed that variations at amino-acid 482 in the ABCG2 gene affect the substrate specificity of the protein, for example rhodamine 123 and daunorubicin are transported only by mutant ABCG2; mutant ABCG2 confers higher level of resistance to certain substrate-drug such as mitoxantrone compared to wild type (Robey et al, 2003)

Summary

Introduction

T-LAK cell-originated protein kinase (TOPK) is a mitogen-activated protein kinase-like kinase (MAPKK), which plays a critical role in facilitating cell cycle control and mitotic progression (Herbert et al, 2018). Dysregulated expression of TOPK often results in cancer development and tumor metastasis in various cancer types (Hansel et al, 2009; Shih et al, 2012; Joel et al, 2015; Ikeda et al, 2016; Jiang et al, 2019). TOPK overexpression promotes cell growth and induces tumor formation (Zhu et al, 2007). Downregulation of TOPK expression suppresses tumor growth, migration, and invasion (Gao et al, 2019). TOPK may be a potential cancerspecific biomarker, and serves as a druggable cancer target with minimal harm to normal tissue (Bellayr et al, 2016; Hayashi et al, 2018; Herbert et al, 2018; Pirovano et al, 2020)

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Conclusion