Targeting the RAF-MEK-ERK pathway in cancer therapy

Cancer Lett. 2009 Oct 8;283(2):125-34. doi: 10.1016/j.canlet.2009.01.022. Epub 2009 Feb 12.


The clinical success of selective kinase inhibitors, such as imatinib and erlotinib, as therapeutic agents for several human cancers has prompted substantial interest in the further development and clinical testing of such inhibitors for a wide variety of malignancies. While much of this effort has been focused on the receptor tyrosine kinases, including EGFR, HER2, PDGF receptor, c-KIT, and MET, inhibitors of serine/threonine kinases are also beginning to emerge within discovery pipelines. Among these kinases, the RAF and MEK kinases have received substantial attention, owing largely to the relatively high frequency of activating mutations of RAS ( approximately 20% of all human cancers), an upstream activator of the well established RAF-MEK-ERK signaling cascade, as well as frequent activating mutations in the BRAF kinase ( approximately 7% of all human cancers). Here, we summarize the current state of development of kinase inhibitors directed at this signaling pathway, a few of which have already demonstrating favorable toxicity profiles as well as promising activity in early phase clinical studies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Clinical Trials as Topic
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases