Journal
BRITISH JOURNAL OF CANCER
Volume 102, Issue 12, Pages 1724-1730Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6605714
Keywords
melanoma; BRAF; resistance; therapy
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Funding
- Melanoma Research Foundation
- Bankhead-Coley Research Program of the State of Florida [09BN-14]
- American Cancer Society [93-032-13]
- Donald A Adam Comprehensive Melanoma Research Center (Moffitt Cancer Center)
- NIH/National Cancer Institute [U54 CA143970-01]
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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. British Journal of Cancer (2010) 102, 1724-1730. doi: 10.1038/sj.bjc.6605714 www.bjcancer.com (C) 2010 Cancer Research UK
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