Overexpression of ABCG2 confers resistance to pevonedistat, an NAE inhibitor.
Exp Cell Res
; 388(2): 111858, 2020 03 15.
Article
en En
| MEDLINE
| ID: mdl-31972220
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Resistencia a Múltiples Medicamentos
/
Resistencia a Antineoplásicos
/
Ciclopentanos
/
Enzimas Activadoras de Ubiquitina
/
Inhibidores Enzimáticos
/
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2
/
Proteínas de Neoplasias
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Exp Cell Res
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos