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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Indoles / pharmacology
  • MAP Kinase Signaling System
  • Melanoma / drug therapy*
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • Time Factors


  • Indoles
  • PLX 4720
  • Sulfonamides
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases