Abstract
The KRAS-G12C inhibitor ARS-1620, is a novel specific covalent inhibitor of KRAS-G12C, possessing a strong targeting inhibitory effect on KRAS-G12C mutant tumors. Overexpression of ATP-binding cassette super-family B member 1 (ABCB1/P-gp) is one of the pivotal factors contributing to multidrug resistance (MDR), and its association with KRAS mutations has been extensively studied. However, the investigations about the connection between the inhibitors of mutant KRAS and the level of ABC transporters are still missing. In this study, we investigated the potential drug resistance mechanism of ARS-1620 associated with ABCB1. The desensitization effect of ARS-1620 was remarkably intensified in both drug-induced ABCB1-overexpressing cancer cells and ABCB1-transfected cells as confirmed by cell viability assay results. This desensitization of ARS-1620 could be completely reversed when co-treated with an ABCB1 reversal agent. In mechanism-based studies, [3H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. Additionally, it was found that ARS-1620 remarkably stimulated ATPase activity of ABCB1, and the HPLC drug accumulation assay displayed that ARS-1620 was actively transported out of ABCB1-overexpressing cancer cells. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications.
Highlights
Multidrug resistance (MDR) has long been considered a major barrier to the success of cancer chemotherapy since it enhanced the survival of cancer cells by attenuating the effectiveness of anticancer drugs (Shen et al, 2008; Paškevičiūtė and Petrikaitė, 2019)
We investigated the connection between novel emerged KRAS-glycine 12 to cysteine (G12C) inhibitor, ARS-1620, and ABCB1overexpressing cancer cells
The overexpression of the ATP-binding cassette (ABC) transporter is one of the causes of multidrug resistance (MDR) in tumor cells leading to chemotherapy failure, and while the relationship between ABC expression level and KRAS mutation in cancer cells can be confirmed (MohelnikovaDuchonova et al, 2013; Wei et al, 2016), the relationship between the expression level of ABC transporters and KRAS inhibitor is not clear, and the effect of ARS-1620 on ABCB1-mediated MDR has not been studied yet
Summary
Multidrug resistance (MDR) has long been considered a major barrier to the success of cancer chemotherapy since it enhanced the survival of cancer cells by attenuating the effectiveness of anticancer drugs (Shen et al, 2008; Paškevičiūtė and Petrikaitė, 2019). The overexpression of ABC transporters in cancer cells accelerates the efflux of chemotherapeutic drugs, resulting in cancer drug resistance, recurrence and death in cancer patients (Gillet and Gottesman, 2010; Wu et al, 2011). The wide use of chemotherapeutic drugs that are substrates of ABCB1 including paclitaxel and doxorubicin could lead to the activation/overexpression of ABCB1, at the same time, the overexpression of ABCB1 confers resistance to these drugs in cancer cells and cancer patients (Genovese et al, 2017). Determining whether existing anticancer drugs are ABCB1 substrates could predict the treatment outcome to develop improved cancer therapy regimens via combination
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