Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma.
Pigment Cell Melanoma Res
; 27(6): 1154-8, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25130256
ABSTRACT
The MEK inhibitor MEK162 is the first targeted therapy agent with clinical activity in patients whose melanomas harbor NRAS mutations; however, median PFS is 3.7 months, suggesting the rapid onset of resistance in the majority of patients. Here, we show that treatment of NRAS-mutant melanoma cell lines with the MEK inhibitors AZD6244 or trametinib resulted in a rebound activation of phospho-ERK (pERK). Functionally, the recovery of signaling was associated with the maintenance of cyclin-D1 expression and therapeutic escape. The combination of a MEK inhibitor with an ERK inhibitor suppressed the recovery of cyclin-D1 expression and was associated with a significant enhancement of apoptosis and the abrogation of clonal outgrowth. The MEK/ERK combination strategy induced greater levels of apoptosis compared with dual MEK/CDK4 or MEK/PI3K inhibition across a panel of cell lines. These data provide the rationale for further investigation of vertically co-targeting the MAPK pathway as a potential treatment option for NRAS-mutant melanoma patients.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema de Sinalização das MAP Quinases
/
Inibidores de Proteínas Quinases
/
GTP Fosfo-Hidrolases
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Melanoma
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Proteínas de Membrana
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Mutação
Limite:
Humans
Idioma:
En
Revista:
Pigment Cell Melanoma Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos