Targeting RAS–ERK signalling in cancer: promises and challenges

ERK signalling is frequently dysregulated in human tumours, usually owing to mutations in RAS or BRAF. Therefore, components of the ERK signalling cascade are attractive targets for drug development.Efforts to directly target mutated RAS have been historically unsuccessful; however, recent reports suggest that the development of RAS inhibitors may be feasible.RAF inhibitors showed improved clinical benefit in the treatment of BRAF mutant (V600E) melanoma, but resistance to treatment frequently develops as a result of increased RAF dimerization and reactivation of ERK signalling.MEK inhibitors have been extensively tested as potential therapeutics for various tumours but with modest results. The efficacy of MEK inhibitors may be limited by recovery of ERK signalling owing to the release of negative feedback and a narrow therapeutic index.The development of ERK inhibitors with promising preclinical antitumour activity has recently been reported. These inhibitors may be effective therapeutics as single agents, or in combinations with RAF and MEK inhibitors.Sustained inhibition of ERK signalling in the tumour may be required for effective treatment of RAS/RAF mutant cancers. This may be achieved by combination strategies that target multiple ERK signalling nodes using drugs with improved biochemical properties.