Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy

Expert Opin Ther Targets. 2012 Jan;16(1):103-19. doi: 10.1517/14728222.2011.645805. Epub 2012 Jan 12.


Introduction: The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials.

Areas covered: The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials.

Expert opinion: Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Signal Transduction / drug effects
  • raf Kinases / metabolism*
  • ras Proteins / metabolism*


  • Antineoplastic Agents
  • raf Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins