The MEK Junction: Protein Presents a Ripe Target for Inhibitors

Jane de Lartigue, PhD
Published: Thursday, Oct 11, 2012

Role of MEK in Signaling Pathways

Graph displaying the Role of MEK

The diagram shows MEK’s position among the key processes of both the MAPK/ERK and the PI3K/Akt/mTOR pathways.

Though located far downstream of the extracellular trigger that initiates its signaling pathway, the MEK protein is no less significant a player in the cascade of events that promotes key cellular processes. Occupying a central role in the mitogen-activated protein kinase (MAPK) pathway and sitting at an important way station accessible to numerous other signaling pathways, MEK is frequently inappropriately activated in many different types of cancer. This has driven interest from the pharmaceutical industry in the development of MEK inhibitors.

While early inhibitors suffered from issues with bioavailability and serious adverse events, newer agents are many times more effective and more specific, and are generating promising results in late-stage clinical trials. Notably, Glaxo- SmithKline’s trametinib recently became the first MEK inhibitor that the FDA is considering for licensing approval.

Marking a Convergence Point

The MAPK pathway transmits signals from growth factors, cytokines, and mitogens through the cell membrane to the nucleus, where they ultimately regulate gene transcription and expression to drive important cellular processes such as proliferation, growth, survival, and motility.

This pathway is regulated by a series of kinases and phosphatases, which add and remove phosphate groups to subsequent kinases in order to propagate a signal through the cell. It begins with the loading of guanosine-5-triphosphate (GTP) onto the Ras protein at the cell surface, followed by sequential activation of a series of protein kinases, ultimately leading to the activation of MAPK (also known as extracellular signal-regulated kinase [ERK]), which phosphorylates various downstream substrates and regulates gene transcription and expression in the nucleus.

MEK stands for the MAPK/ERK kinase, and it is among the series of regulatory kinases targeting that pathway. It has a dual role, acting as both a serine/threonine kinase and a tyrosine kinase. MEK is also part of a chain involving multiple other important signaling pathways that channel into the MAPK pathway, including—and probably most significantly—the phosphatidylinositol-3-kinase (PI3K)-Akt/mammalian target of rapamycin (mTOR) pathway. Thus, MEK makes a useful potential target for small-molecule inhibitors, whereby we might be able to switch off a variety of cell signaling pathways that are implicated in cancer.

Inhibiting MEK in Cancer

In addition to direct mutations in the MEK protein, many of the other mutations frequently found in human cancer result in inappropriate activation of MEK. Genetic mutations in the BRAF gene are found in 60% of melanomas and in various other cancer types, and this frequently has the effect of further activating MEK.

The BRAF gene encodes the B-Raf protein, a member of the Raf kinase family, which functions upstream of MEK in the MAPK pathway. Indeed, preclinical studies indicated that BRAF-mutant tumor-derived cell lines are highly sensitive to MEK inhibitors. Ras is inappropriately activated in approximately one-third of all human cancers. MEK is also often constitutively active in acute myelogenous leukemia/ acute lymphoblastic leukemia (AML/ALL), and a recent study observed activation of the MEK pathway in 100% of hepatocellular carcinoma (HCC) specimens.

The central role of MEK in the MAPK pathway and downstream of numerous other important signaling pathways, in addition to the observation that it is frequently activated in a variety of human cancers, served as a call to pharmaceutical companies to generate specific inhibitors of MEK for cancer therapy.

Early MEK inhibitors faced problems with bioavailability and serious ocular adverse events. and development of many agents, including CI-1040 and PD0325901, was discontinued due to disappointing results in phase II clinical testing. Newer agents are demonstrating much improved pharmacological properties and are at least 10 to 100 times more effective, meaning that they can be used at lower concentrations to help avoid serious toxicity.

A number of MEK inhibitors are currently under development for the treatment of a wide variety of different cancers (Below). MEK inhibitors differ from other kinase inhibitors in that they do not compete with adenosine triphosphate (ATP) binding and are thus non-ATP competitive. In addition, most of the MEK inhibitors under evaluation are also specific for MEK and do not inhibit other kinases, which should help to limit their side effects.


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