Overexpression of ABCG2 confers resistance to pevonedistat, an NAE inhibitor

Pevonedistat is a potent, selective, first-in-class NEDD8 activating enzyme inhibitor. It is now under multiple clinical trials that investigate its anticancer effect against solid tumors and leukemia. ATP-binding cassette (ABC) transporters are membrane proteins that are involved in mediating multi...

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Bibliographic Details
Published in:Experimental cell research 2020-03, Vol.388 (2), p.111858-111858, Article 111858
Main Authors: Wei, Liu-Ya, Wu, Zhuo-Xun, Yang, Yang, Zhao, Min, Ma, Xiang-Yu, Li, Jin-Sui, Yang, Dong-Hua, Chen, Zhe-Sheng, Fan, Ying-Fang
Format: Article
Language:English
Subjects:
ABCG2
ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism
Cyclopentanes - pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Enzyme Inhibitors - pharmacology
Humans
MLN4924
Multidrug resistance
NEDD8 activating enzyme inhibitor
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Pevonedistat
Pyrimidines - pharmacology
Tumor Cells, Cultured
Ubiquitin-Activating Enzymes - antagonists & inhibitors
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Summary:Pevonedistat is a potent, selective, first-in-class NEDD8 activating enzyme inhibitor. It is now under multiple clinical trials that investigate its anticancer effect against solid tumors and leukemia. ATP-binding cassette (ABC) transporters are membrane proteins that are involved in mediating multidrug resistance (MDR). In this article, we reveal that pevonedistat is a substrate of ABCG2 which decreases the therapeutic effect of pevonedistat. The cytotoxicity of pevonedistat was significantly weakened in ABCG2-overexpressing cells, and the drug resistance can be reversed by ABCG2 inhibitors. The ATPase assay suggested that pevonedistat can stimulate ABCG2 ATPase activity in a concentration-dependent manner. Pevonedistat showed little effect on the expression level or subcellular localization of ABCG2 after 72 h treatment. Furthermore, a pevonedistat resistance cell line S1-PR was established and overexpressed ABCG2. Generally, our study provides evidence that ABCG2 can be a prominent factor leading to pevonedistat-resistance. Furthermore, ABCG2 may also be utilized as a biomarker to monitor the development of pevonedistat resistance during cancer treatment.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2020.111858