A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status

Pigment Cell Melanoma Res. 2011 Apr;24(2):326-33. doi: 10.1111/j.1755-148X.2010.00823.x. Epub 2011 Jan 12.


Oncogenic mutations within the MAPK pathway are frequent in melanoma, and targeting of MAPK signaling has yielded spectacular responses in a significant number of patients that last for several months before relapsing. We investigated the effects of two different inhibitors of MAPK signaling in proliferative and invasive melanoma cell cultures with various mutations in the MAPK pathway. Proliferative melanoma cells were more susceptible to pathway inhibition than invasive phenotype cells, irrespective of BRAF mutation status, while invasive phenotype cell response was dependent on BRAF mutation status. Critically, MAPK pathway inhibition of proliferative phenotype cells resulted in acquisition of invasive phenotype characteristics. These results show that melanoma cell phenotype is an important factor in MAPK pathway inhibition response. This suggests that while current therapeutic strategies target proliferative melanoma cells, future approaches should also account for the invasive phenotype population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Proliferation
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gene Expression Profiling
  • Humans
  • MAP Kinase Signaling System / physiology
  • Male
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Microarray Analysis
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Neoplasm Invasiveness
  • Phenotype*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • raf Kinases / antagonists & inhibitors*


  • Enzyme Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • raf Kinases
  • Mitogen-Activated Protein Kinase Kinases