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Targeting RAS–ERK signalling in cancer: promises and challenges

Key Points

  • 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.

Abstract

The RAS–RAF–MEK–ERK signalling pathway is hyperactivated in a high percentage of tumours, most frequently owing to activating mutations of the KRAS, NRAS and BRAF genes. Recently, the use of compounds targeting components of ERK signalling, such as RAF or MEK inhibitors, has led to substantial improvement in clinical outcome in metastatic melanoma and has shown promising clinical activity in additional tumour types. However, response rates are highly variable and the efficacy of these drugs is primarily limited by the development of resistance. Both intrinsic and acquired resistance to RAF and MEK inhibitors are frequently associated with the persistence of ERK signalling in the presence of the drug, implying the need for more innovative approaches to target the pathway.

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Figure 1: Current targeting strategies of the RAS–ERK signalling pathway.
Figure 2: RAF dimerization is a critical determinant of response to RAF inhibitors.
Figure 3: Modes of target inhibition by MEK and ERK inhibitors.
Figure 4: Major mechanisms of adaptive response or acquired resistance to RAF and MEK inhibitors.

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Acknowledgements

P.I.P. received support by the Harry J. Lloyd Charitable Trust, a Tisch Cancer Institute Developmental Award, a CY14 Developmental Research Pilot Project Program, a TCI Young Cancer Research Award and a Career Development Award by the Dermatology Foundation. The authors thank S. Chandarlapaty (Memorial Sloan-Kettering Cancer Center) for critical reading of the manuscript.

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Samatar, A., Poulikakos, P. Targeting RAS–ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 13, 928–942 (2014). https://doi.org/10.1038/nrd4281

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