Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition.
Pigment Cell Melanoma Res
; 25(2): 248-58, 2012 Mar.
Article
em En
| MEDLINE
| ID: mdl-22171948
ABSTRACT
BRAF inhibition is highly active in BRAF-mutant melanoma, but the degree and duration of responses is quite variable. Improved understanding of the mechanisms of de novo resistance may lead to rational therapeutic strategies with improved efficacy. Proteomic analysis of BRAF-mutant, PTEN-wild-type human melanoma cell lines treated with PLX4720 demonstrated that sensitive and de novo resistant lines exhibit similar RAS-RAF-MEK-ERK pathway inhibition, but the resistant cells exhibited durable activation of S6 and P70S6K. Treatment with the mTOR inhibitor rapamycin blocked activation of P70S6K and S6, but it also increased activation of AKT and failed to induce cell death. Combined treatment with rapamycin and PX-866, a PI3K inhibitor, blocked the activation of S6 and AKT and resulted in marked cell death when combined with PLX4720. The results support the rationale for combined targeting of BRAF and the PI3K-AKT pathways and illustrate how target selection will be critical to such strategies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Resistencia a Medicamentos Antineoplásicos
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Fosfatidilinositol 3-Quinases
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Proteínas Proto-Oncogênicas B-raf
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Inibidores de Proteínas Quinases
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Serina-Treonina Quinases TOR
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Terapia de Alvo Molecular
Limite:
Humans
Idioma:
En
Revista:
Pigment Cell Melanoma Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos