MEK and RAF inhibitors for BRAF-mutated cancers

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,NRASandHRAS), 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.