Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

ESMO 2014 Pathway of the Day: RAS/RAF/MEK/ERK

The RAS/RAF/MEK/ERK pathway regulates key cellular functions including proliferation, survival, differentiation, angiogenesis and migration.
27 Sep 2014
Pathology/Molecular biology
Caroline Robert, Institut Gustave Roussy, Paris, France
Caroline Robert

Caroline Robert

Article extracted from the ESMO 2014 onsite newspaper.

The RAS/RAF/MEK/ERK pathway (also known as the MAPK pathway; see figure) regulates key cellular functions including proliferation, survival, differentiation, angiogenesis and migration. Activation of the pathway at the cell surface is initiated by ligand binding to receptor tyrosine kinases. The resulting signal cascades sequentially via RAS, RAF, mitogen-activated protein kinase (MEK) and finally extracellular signal-regulated kinase (ERK); the latter regulates gene transcription in the cell nucleus.

Activating point mutations of RAS genes (most often the KRAS variant) are generally acquired early in tumourigenesis and are found in approximately 30% of human cancers, such as pancreatic, colorectal and lung cancers.

Three variants of the RAF gene exist, which encode for the respective ARAF, BRAF and RAF-1 (or CRAF) proteins. Mutations in the serine threonine kinase gene, BRAF, occur frequently in a number of cancers, particularly melanoma, papillary thyroid, colon and serous ovarian cancers. The second-generation BRAF inhibitors, dabrafenib and vemurafenib, are approved for the treatment of advanced melanoma.

Although MEK gene mutations occur rarely and are associated with a small proportion of melanoma, lung and colon cancers, MEK is a key downstream protein in the RAS/RAF/MEK/ERK pathway and thus a prime target for inhibitor therapy. Sensitivity to MEK inhibitors is enhanced in tumour cells harbouring RAS pathway mutations. The MEK inhibitor, trametinib, is approved for the treatment of BRAF-mutated melanoma. Improved clinical benefit has been demonstrated with combined BRAF and MEK inhibitor therapy. For instance, dabrafenib/trametinib combination enhances response rates and progression-free survival in advanced melanoma.1

MAPK Pathway

Model of the ERK1/2 MAPK signaling network controlled by receptor tyrosine kinases and Ras. Clin Cancer Res 2014;20:2516–22.


1Flaherty KT, et al. N Engl J Med 2012;367:1694–703

Last update: 27 Sep 2014

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings