Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.
Br J Cancer
; 102(12): 1724-30, 2010 Jun 08.
Article
en En
| MEDLINE
| ID: mdl-20531415
BACKGROUND: Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required. METHODS: The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture. RESULTS: BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance. CONCLUSION: Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Resistencia a Antineoplásicos
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Proteínas Proto-Oncogénicas B-raf
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Quinasas MAP Reguladas por Señal Extracelular
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Melanoma
Límite:
Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido