Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Br J Cancer. 2018 Jan;118(1):3-8. doi: 10.1038/bjc.2017.399. Epub 2017 Dec 14.


The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In particular, issues related to the dimerisation of the Raf kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. Here, we will review the importance of Raf dimerisation in cell signalling as well as its effects on Raf inhibitor therapy, and we will present the new strategies that are being pursued to overcome the 'Raf Dimer Dilemma'.

Publication types

  • Review

MeSH terms

  • Drug Resistance, Neoplasm
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Models, Molecular
  • Molecular Targeted Therapy
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Oximes / pharmacology
  • Oximes / therapeutic use
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Multimerization
  • Signal Transduction
  • Vemurafenib / pharmacology
  • Vemurafenib / therapeutic use
  • raf Kinases / antagonists & inhibitors
  • raf Kinases / chemistry*
  • raf Kinases / genetics


  • Imidazoles
  • Oximes
  • Protein Kinase Inhibitors
  • Vemurafenib
  • raf Kinases
  • dabrafenib