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MEK and RAF inhibitors for BRAF-mutated cancers

Published online by Cambridge University Press:  12 October 2012

Sarah Belden  and
Keith T. Flaherty
Sarah Belden
Affiliation:
Massachusetts General Hospital Cancer Center, Boston, MA, USA University of New England College of Osteopathic Medicine, Biddeford, ME, USA
Keith T. Flaherty*
Affiliation:
Massachusetts General Hospital Cancer Center, Boston, MA, USA
*
*Corresponding author: Keith T. Flaherty, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 9E, Boston, MA 02114, USA. E-mail: [email protected]
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Abstract

The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of many cancers. Under normal physiologic conditions, the RAS–RAF–mitogen-activated protein kinase kinase (MEK)–mitogen-activated protein kinase (ERK) signalling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its cognate growth factor. It has been demonstrated in many systems that aberrant autocrine or paracrine stimulation of growth factor receptors is pathogenic in large part because of MAPK activation. As one of the key downstream effector pathways of mutated RAS (KRAS, NRAS and HRAS), pharmacologic inhibition of components of the MAPK pathway has been pursued as a means to indirectly inhibit RAS, which remains a technical challenge for direct pharmacologic inhibition. RAF and MEK are the two non-membrane-bound, serine–threonine and tyrosine–threonine kinases, within the pathway that have been most extensively explored as drug targets. The discovery of activating BRAF mutations in cancer clarified which cancer types and subsets of certain cancers are most dependent on activation of the MAPK pathway for growth and survival. Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e17
Copyright
Copyright © Cambridge University Press 2012

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References

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Further reading

http://mmdm.cancercommons.org/ml/index.php/A_Melanoma_Molecular_Disease_ModelGoogle Scholar