Overexpression of ABCG2 confers resistance to pevonedistat, an NAE inhibitor

Exp Cell Res. 2020 Mar 15;388(2):111858. doi: 10.1016/j.yexcr.2020.111858. Epub 2020 Jan 20.

Abstract

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.

Keywords: ABCG2; MLN4924; Multidrug resistance; NEDD8 activating enzyme inhibitor; Pevonedistat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Pyrimidines / pharmacology*
  • Tumor Cells, Cultured
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors*

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Cyclopentanes
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Pyrimidines
  • Ubiquitin-Activating Enzymes
  • NAE protein, human
  • pevonedistat