The RAS-regulated RAF–MEK–ERK signalling pathway transmits signals from growth factor receptors to the nucleus and other organelles to regulate cell proliferation, differentiation, survival and invasion.
ERK pathway architecture places MEK1 and MEK2 in a unique position, where they process inputs from multiple upstream activating kinases so that ERK1 and ERK2 may be activated alone (following RAF activation) or together with other kinases such as JNK or p38.
The majority of cancers exhibit hyper-activation of the ERK pathway owing to deregulation (mutation, gene fusions, amplification, and so on) of receptor tyrosine kinases, RAS, BRAF, CRAF, MEK1 or MEK2 or owing to the loss of negative pathway regulators, such as dual-specificity phosphatases (DUSPs) and NF1. In many cases, these mutations confer a range of pathway dependencies including classical 'oncogene addiction', providing a rationale for ERK pathway inhibitors as therapeutic agents.
Melanomas carrying the mutation encoding BRAF-V600E are almost invariably addicted to BRAF activity, and first-generation BRAF inhibitors (BRAFis) have transformed the treatment of this disease. However, an inability to inhibit signalling by RAF dimers drives acquired resistance, and paradoxical RAF activation in tumours with wild-type BRAF limits the success or wider application of BRAFis.
As RAF signalling proceeds via the activation of MEK1 and MEK2, and RAF-addicted tumour cells are also MEK-addicted, MEK1 and MEK2 are also attractive drug targets. Additionally, MEK1 and MEK2 contain a unique hydrophobic pocket adjacent to their ATP-binding site, which allows the binding of potent, non-ATP competitive, allosteric inhibitors. However, MEK1 and MEK2 are rarely mutated in cancer, so MEK inhibitors (MEKis) will not preferentially inhibit MEK1 and MEK2 in tumour cells compared with normal tissue; this may contribute to normal tissue toxicity.
The first MEKi to receive US Food and Drug Administration approval, trametinib, is being used to treat BRAF-mutant melanoma in combination with first-generation BRAFis. A range of additional MEKis are in late-stage clinical development and exhibit various modes of action; for example, some MEKis can prevent the phosphorylation of MEK1 and MEK2 by RAF, and others can disrupt RAF–MEK1/MEK2 complexes. The extent to which these properties influence clinical activity is currently unclear.
Factors that limit the efficacy of MEKis include loss of feedback inhibition and consequent reactivation of ERK1 and ERK2. Intrinsic resistance can be driven by the activation of parallel pathways, including the PI3K pathway, whereas acquired resistance to MEKis arises through the emergence of mutations in MEK1 or MEK2 or the amplification of BRAFV600E or mutant RAS.
Adaptation and resistance to MEKis can be overcome by combinations with other targeted agents, including intrapathway dual inhibition. Clinical trials assessing MEKis in combination with other targeted agents or conventional chemotherapy are ongoing.
The role of the ERK signalling pathway in cancer is thought to be most prominent in tumours in which mutations in the receptor tyrosine kinases RAS, BRAF, CRAF, MEK1 or MEK2 drive growth factor-independent ERK1 and ERK2 activation and thence inappropriate cell proliferation and survival. New drugs that inhibit RAF or MEK1 and MEK2 have recently been approved or are currently undergoing late-stage clinical evaluation. In this Review, we consider the ERK pathway, focusing particularly on the role of MEK1 and MEK2, the 'gatekeepers' of ERK1/2 activity. We discuss their validation as drug targets, the merits of targeting MEK1 and MEK2 versus BRAF and the mechanisms of action of different inhibitors of MEK1 and MEK2. We also consider how some of the systems-level properties (intrapathway regulatory loops and wider signalling network connections) of the ERK pathway present a challenge for the success of MEK1 and MEK2 inhibitors, discuss mechanisms of resistance to these inhibitors, and review their clinical progress.
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The authors thank J. Sebolt-Leopold who provided information as a personal communication and apologize to those whose work was not included owing to space limitations.
P.D.S. is a paid employee and shareholder of AstraZeneca. Some work in S.J.C.'s laboratory is supported by a sponsored research collaboration funded by AstraZeneca; however, S.J.C. receives no personal payment of any kind from AstraZeneca. C.J.C. and M.J.S. declare no competing interests.
Supplementary information S1 (figure) | Whilst RAF proteins were the first 'MEK activators' to be described, they are a subset of the MEK activators in cells. (PDF 309 kb)
A cocktail of two protein kinase inhibitors, one inhibiting MEK1 and MEK2, and the other inhibiting glycogen synthase kinase 3 (GSK3).
- Allosteric inhibitor
A small molecule that inhibits the activity of an enzyme by binding to a regulatory site that is distinct from the active or catalytic site.
- MEK addiction
How dependent on MEK1/2 activity a tumour cell is for survival and proliferation; it can broadly be measured by how sensitive a tumour cell is to a MEK inhibitor.
- Feedback relief
ERK1/2-catalysed feedback phosphorylation and inhibition of RAF normally operates in the pathway but is relieved when MEK1/2 are inhibited and ERK1/2 activity declines, resulting in the activation of RAF and further MEK1/2 phosphorylation. Pathway activity also stimulates the expression of negative regulators of pathway activity such as the ERK phosphatase DUSP6; expression of these negative regulators is reduced when the pathway is inhibited.
- Feedback buster
A term adopted by the field, although something of a misnomer. All MEK inhibitors (MEKis) relieve ERK-dependent negative feedback to RAF, resulting in RAF activation. Feedback buster MEKis mitigate some, but not all, consequences of feedback relief that arise when ERK is inhibited by interfering with the phosphorylation of MEK by RAF, thereby reducing rebound activation of the pathway. By contrast, conventional MEKis do not prevent MEK phosphorylation by RAF.
- Phosphomimetic mutant
A phosphomimetic mutant of MEK1 exhibits constitutive (MAP3K-independent) activation owing to acidic substitutions at Ser218 and Ser222 in the activation loop that mimic the negative charge of phosphorylation.
A DNA-alkylating agent that has commonly been used as a single agent in the treatment of metastatic melanoma.
- Plexiform neurofibromatosis
A non-cancerous hyperproliferative disease of the nerve sheath that is driven by the loss of the NF1 tumour suppressor.
A neoadjuvant therapy is treatment given before primary therapy; in the context of this Review, selumetinib is administered first as adjuvant therapy and continued until the radioactive iodine therapy has been administered.
Refers to a transcriptomic signature that reports activation of the RAS pathway and may predict responses to RAS pathway drugs.
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Caunt, C., Sale, M., Smith, P. et al. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 15, 577–592 (2015). https://doi.org/10.1038/nrc4000
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