Mutant BRAF melanomas--dependence and resistance

Cancer Cell. 2011 Jan 18;19(1):11-5. doi: 10.1016/j.ccr.2011.01.008.


RAF inhibitors have the unique property of transactivating RAS-dependent RAF dimers in most cells but inhibit RAF/MEK/ERK signaling in cells expressing mutant BRAF, in which RAS activity is too low to support this process. These drugs thus selectively inhibit ERK signaling in tumors with BRAF mutation. RAF inhibitors have remarkable clinical activity in melanomas with BRAFV600E mutations; however, resistance invariably develops. Three recent papers reveal that acquired resistance may be due to mechanisms that cause ERK signaling to become insensitive to RAF inhibitors, or that reduce the dependence of the tumor on ERK signaling through activation of other pathways.

Publication types

  • Review

MeSH terms

  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Protein Kinase Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf