Oncology Live®
September 2012
Volume 13
Issue 9

The MEK Junction: Protein Presents a Ripe Target for Inhibitors

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.

Role of MEK in Signaling Pathways

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.

Aiming for Double Trouble

Many studies are examining the therapeutic potential of combining MEK inhibitors with other targeted therapies. The vast majority of these studies indicate that adding MEK inhibitors into the mix results in improved outcomes and that they have additive or synergistic effects when used in combination with other targeted agents (eg, PI3K, Akt, mTOR, and BRAF inhibitors), as well as chemotherapy, radiation therapy, and hormonal therapy.

As with other kinase inhibitor therapies, tumor cells can develop resistance, and acquired resistance to MEK inhibitors has already been documented. In an effort to uncover possible mechanisms of this resistance, researchers have discovered that many of these mechanisms lead to reactivation of the MAPK pathway, despite the presence of the MEK inhibitor. A recent study found that amplification of mutant BRAF or KRAS, as well as point mutations in the MEK gene itself, was responsible for acquired resistance to the MEK inhibitor MEK6244 in BRAF- or KRAS-mutant colorectal cancer cells. This has provided the rationale for studying a combination of MEK and BRAF inhibitors, which could help to overcome resistance. Such studies are already under way and have shown very promising initial results, particularly a combination of trametinib with the BRAF inhibitor dabrafenib in metastatic melanoma.

Since BRAF amplification is thought to drive MEK inhibitor resistance via hyperactivation of MEK (increased levels of phosphorylated MEK were observed in resistant cells), it is possible that other alterations to components of the pathway may have a similar effect. In fact, activating mutations in the PI3K gene have been shown to reduce the sensitivity of tumor cells to MEK inhibitors, while cells containing Ras or EGFR mutations are resistant. As such, other combinatorial regimens are being evaluated that incorporate MEK inhibitors and inhibitors of other components of the MAPK pathway or parallel pathways, including PI3K, AKT, and ERK inhibitors.

Finally, using combination therapy that incorporates MEK inhibitors also could help to overcome resistance to other targeted agents, or to enhance the therapeutic effects of more traditional therapies. Activation of Ras, MEK, and ERK has been observed in leukemia cells that are resistant to the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib; thus, the addition of a MEK inhibitor could help to combat this resistance. A consequence of chemotherapy in breast, hematopoietic, prostate, and other cancers is the induction of ERK; therefore, MEK inhibitors could be used to prevent resistance and augment the effects of chemotherapy.

MEK-Targeted Therapies in Development

Regulatory Review/Later-Stage Trials



Trametinib (GSK1120212) is undergoing phase III testing in patients with advanced or metastatic melanoma. The METRIC trial compares standard chemotherapy (dacarbazine or paclitaxel) to trametinib in more than 300 patients. Promising results from this trial were presented at the 2012 American Society of Clinical Oncology (ASCO) meeting in June. A 55% reduction in the risk of progression in patients taking trametinib was demonstrated, with a progression-free survival (PFS) of 4.8 months compared with 1.5 months in patients on the chemotherapy regimen. The response rates were 22% versus 8%, respectively, and trametinib was well tolerated. In August, GlaxoSmithKline filed a New Drug Application (NDA) with the FDA for approval of trametinib in patients with unresectable metastatic melanoma with BRAF V600 mutations.

Trametinib is also being evaluated in phase II trials in patients with relapsed/refractory leukemias and in phase III trials in combination with the BRAF inhibitor dabrafenib. Preliminary data from the latter trial indicated that this combination may help to overcome the resistance and toxicity associated with BRAF inhibitor monotherapy; PFS was 10.8 months, objective response rate was 56%, and there was a decrease in the incidence of hyperproliferative skin lesions, squamous cell carcinoma, and actinic keratosis in the combination treatment arm. (NCT00920140, NCT01584648)

Phase I/II Studies


(Novartis/Array BioPharma)

MEK162 is currently being evaluated in phase I and II studies in a variety of different tumor types, including advanced solid tumors, and epithelial ovarian, fallopian tube, and peritoneal cancers, and in phase II studies in patients with advanced melanoma. Preclinical testing indicated that this agent is active against BRAF V600E or NRAS-mutant melanoma, making it the first targeted therapy to demonstrate activity in NRAS-mutant patients. (NCT00959127, NCT01649336, NCT01320085)


(AstraZeneca/Array BioPharma/ National Cancer Institute/ Cancer

Research UK)

Selumetinib is being developed through a collaboration between AstraZeneca and Array BioPharma. The agent, also known as AZD6244 and ARRY-142886, was originally tested in patients with melanoma, colon cancer, non-small cell lung cancer (NSCLC), and pancreatic cancer. It was discontinued in these trials when it failed to show therapeutic distinction over the chemotherapeutic agent temozolomide.

Development has subsequently continued in various other cancer types, both as monotherapy and in combination with other agents, and it is soon to enter phase III clinical testing. Currently, phase II trials are ongoing as monotherapy in patients with multiple myeloma, in combination with the epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with wild-type and KRAS-mutant NSCLC, and with the Akt inhibitor MK-2206 in relapsed advanced melanoma patients with the BRAF V600E mutation. Phase I tests of selumetinib combined with the vascular endothelial growth factor receptor (VEGFR)/EGFR inhibitor vandetanib in patients with solid tumors and NSCLC are also being carried out. (NCT01085214, NCT01229150, NCT01510444, NCT01586624)

BAY 86-9766

(Bayer HealthCare)

This agent, formerly known as RDEA119, is currently being evaluated in a phase I/II trial in combination with gemcitabine in patients with advanced pancreatic cancer and in the phase II BASIL trial with the tyrosine kinase inhibitor sorafenib for the treatment of patients with liver cancer. (NCT01251640, NCT01204177)


(EMD Serono)

EMD Serono is examining the efficacy of MEK inhibitor AS703026 in a phase I/II clinical trial in patients with acute myelogenous leukemia (AML) and other hematological malignancies. (NCT00957580)



Phase I testing of MEK inhibitor GDC-0973 is currently under way in combination with other agents in locally advanced and metastatic solid tumors, including with an Akt inhibitor (in collaboration with Exelixis) and with a phosphatidylinositol-3-kinase (PI3K) inhibitor. In addition, the agent is being paired with the BRAF inhibitor vemurafenib in metastatic melanoma. (NCT01562275, NCT00996892, NCT01271803)


(Millennium: The Takeda Oncology Company)

TAK-733 is currently undergoing phase I trials in patients with advanced nonhematological malignancies, as monotherapy and in combination with the Aurora A kinase inhibitor alisertib (MLN8237). (NCT00948467, NCT01613261)

Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

Key Research

  • Chappell WH, Steelman LS, Long JM, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health [review]. Oncotarget. 2011; 2(3): 135-164.
  • Hatzivassiliou G, Liu B, O’Brien C, et al. ERK inhibition overcomes acquired resistance to MEK inhibitors [published online ahead of print March 8, 2012]. Mol Cancer Ther. 2012;11(5):1143-1154. doi:10.1158/1535-7163.MCT-11-1010.
  • Kohno M, Tanimura S, and Ozaki K. Targeting the extracellular signal-regulated kinase pathway in cancer therapy [review]. Biol Pharm Bull. 2011;34(12):1781-1784.
  • Martin-Sanchez E, Rodriguez-Pinilla SM, Sanchez-Beato M, et al. Simultaneous pan-PI3K and MEK inhibition as a potential therapeutic strategy in peripheral T cell lymphomas [published online ahead of print July 16, 2012]. Haematologica. doi:10.3324/haematol.2012.068510.
  • McCubrey JA, Steelman LS, Abrams SL, et al. Emerging MEK inhibitors. Expert Opin Emerg Drugs. 2010;15(2):203-223.
  • Messersmith WA, Hidalgo M, Carducci M, et al. Novel targets in solid tumors: MEK inhibitors. Clin Adv Hematol Oncol. 2006;4(11):831-836.
  • Packer LM, Rana S, Hayward R, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2011;20:715-727.
  • Poulikakos PI, Solit DB. Resistance to MEK inhibitors: should we co-target upstream? Sci Signal. 2011;4(166):pe16.
  • Trujillo JI. MEK inhibitors: a patent review 2008-2010 [published online ahead of print May 9, 2011]. Expert Opin Ther Pat. 2011;21(7):1045-1069. doi:10.1517/13543776.2011.577068.

Related Videos
Nikhil Khushalani, MD, vice chair, Department of Cutaneous Oncology, Moffitt Cancer Center
Salman R. Punekar, MD
Axel Hauschild, MD, PhD, head, Skin Cancer Trial Center, University Hospital Schleswig-Holstein
Ahmad Tarhini, MD, PhD
Thomas Marron, MD, PhD
Nivolumab plus relatlimab vs nivolumab in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): overall survival and melanoma-specific survival outcomes at 3 years
Long-term follow up for adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma: Final results of the COMBI-AD study
 Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases
D. Ross Camidge, MD, PhD
D. Ross Camidge, MD, PhD