Raf kinase as a target for anticancer therapeutics

Mol Cancer Ther. 2005 Apr;4(4):677-85. doi: 10.1158/1535-7163.MCT-04-0297.

Abstract

The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors. This review will provide an overview of the ERK signaling pathway in normal and neoplastic tissue, with a specific focus on novel therapies targeting the ERK pathway at the level of Raf kinase.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Benzenesulfonates / pharmacology
  • Carcinoma, Renal Cell / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Membrane Proteins / metabolism
  • Models, Biological
  • Neovascularization, Pathologic
  • Niacinamide / analogs & derivatives
  • Oligonucleotides, Antisense / pharmacology
  • Phenylurea Compounds
  • Phosphorylation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-kit / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism*
  • Pyridines / pharmacology
  • Signal Transduction
  • Sorafenib
  • Time Factors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Enzyme Inhibitors
  • Membrane Proteins
  • Oligonucleotides, Antisense
  • Phenylurea Compounds
  • Pyridines
  • flt3 ligand protein
  • Niacinamide
  • Sorafenib
  • Proto-Oncogene Proteins c-kit
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases