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Br J Cancer. 2010 Jun 8;102(12):1724-30. doi: 10.1038/sj.bjc.6605714.

Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.

Author information

1
Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.

Abstract

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.

PMID:
20531415
PMCID:
PMC2883709
DOI:
10.1038/sj.bjc.6605714
[Indexed for MEDLINE]
Free PMC Article

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