The RAS/RAF/MEK/ERK pathway is one of the most frequently dysregulated signal transduction pathways in cancer, with aberrant activation occurring in more than 30% of human cancers. Mutations in KRAS have been found in 90% of pancreatic cancers, 20% of non–small cell lung cancers (NSCLC), and up to 50% of colorectal and thyroid cancers. Mutations of BRAF have been identified in more than 60% of melanomas and 40%-60% of papillary thyroid cancers.
As links in this signaling cascade, MEK1 and MEK2 play crucial roles in tumorigenesis, cell proliferation, and inhibition of apoptosis. Although MEK1/2 are themselves rarely mutated, constitutively active MEK has been found in more than 30% of primary tumor cell lines tested. Inhibition of MEK has, therefore, been an attractive target for development of pharmaceutical therapies.
What is the MEK Pathway?
The RAS/RAF/MEK/ERK cell signaling pathway is a chain of proteins that carries signals from cell surface receptors to the DNA. (For more information about the RAS/RAF/MEK/ERK pathway, read Exploring the Pathway: The RAS/RAF/MEK/ERK Pathway Fact Sheet.) The pathway is activated by a number of growth factors and cytokines through receptor tyrosine kinases. This results in activation of RAS, which then recruits RAF, which is in turn activated by multiple phosphorylation events.
Activated RAF phosphorylates and activates MEK kinase, which in turn phosphorylates and activates ERK kinase. The phosphorylated ERK can then translocate to the nucleus, where it phosphorylates and activates various transcription factors. This process leads to altered gene transcription and cellular proliferation. One of the ways of halting this cascade is the inhibition of MEK.
Inhibition of MEK
Because of the importance of the RAS/RAF/MEK/ERK pathway in cancer, it is one of the most thoroughly studied cell signaling pathways. Two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib) have been approved by the U.S. Food and Drug Administration (FDA) for treatment of BRAF-mutated melanoma. Numerous other entities have been investigated as potential MEK inhibitors, and these are detailed briefly in this fact sheet.
One of the attractive features of MEK as a target of inhibition is its structure. It contains a pocket structure, conserved only in MEK proteins, that, upon binding by an inhibitor, results in locking unphosphorylated MEK1/2 into a catalytically inactive state. Because this action does not have an inhibitory effect on the highly conserved adenosine triphosphate binding site pocket, it avoids side effects associated with inhibition of other protein kinases. Several compounds with potent inhibitory activity specific for MEK1/2 have been investigated.
The first MEK inhibitor entered clinical trials in 2000, but until 2014 no MEK inhibitor had been approved for clinical use. This is because, for the most part, the agents investigated have not demonstrated robust clinical activity in most tumor types. In addition, a number of mechanism-based toxicities have been seen.
CI-1040 (PD184352) was the first MEK inhibitor to enter clinical trials. It advanced as far as a phase II study in patients with a variety of cancer types, but no objective response was seen in patients in the study. Its development was halted.
A structural analogue of CI-1040, PD0325901, possessed improved oral bioavailability and markedly increased potency against MEK1/2. Evidence of antitumor activity was seen in patients with melanoma in a phase I study, but enrollment was stopped because of retinal vein occlusion. In a phase II study in patients with previously treated NSCLC, the primary efficacy endpoint was not met.
Selumetinib is one of the most widely clinically studied MEK inhibitors. Single-agent selumetinib has been evaluated in multiple phase II studies in a variety of solid tumors and hematologic malignancies. Results of single-agent clinical trials have been mixed, with, for example, some objective responses and stable disease seen in patients with metastatic biliary cancers but no significant antitumor activity in patients with papillary thyroid carcinoma or hepatocellular carcinoma. In randomized phase II studies comparing selumetinib with other anticancer agents, superiority was not demonstrated, although anticancer activity of single-agent selumetinib was seen in each study. Selumetinib has also been assessed in multiple trials in combination with other targeted or conventional chemotherapy anticancer agents; trials of combinations with agents including vandetanib, cixutumumab, docetaxel, gemcitabine, and irinotecan are ongoing or have been completed.
Cobimetinib (formerly GDC-0973) was combined with vemurafenib in a phase Ib study in patients with BRAFV600-mutated melanoma. Positive results of this study led to a phase III trial of the combination of cobimetinib and vemurafenib in patients with previously untreated unresectable locally advanced or metastatic melanoma harboring a BRAFV600mutation. The trial met its primary endpoint, demonstrating a statistically significant increase in progression-free survival (PFS) for the combination compared with vemurafenib alone. Based on these results, regulatory approval of the combination is being sought in Europe and the United States. Phase I and II trials assessing the combination in other settings are ongoing, as are trials of cobimetinib in combination with other agents.
Refametinib (BAY 86-9766) was well tolerated in a phase I study. In a phase II study in combination with sorafenib for treatment of unresectable hepatocellular cancer, among 70 patients, three had confirmed partial response and 25 had prolonged stable disease; however, the level of adverse events was high. In a single-arm, open-label, phase IIa study in patients with advanced pancreatic cancer, the combination of refametinib and gemcitabine was active, with an acceptable safety profile, according to a presentation at the 2014 ASCO Annual Meeting (Abstract 4025). A trend toward improved outcomes in patients with KRAS wild-type pancreatic cancer was observed. Although this trial is completed, the results have not yet been published. In a phase I trial combining refametinib with the PI3K inhibitor copanlisib (BAY 80-6946), the combination was generally well tolerated, and preliminary evidence of clinical efficacy was observed (2014 ASCO Annual Meeting, Abstract 2588).
Trametinib received FDA approval in 2014 for treatment of unresectable melanoma with BRAFV600Eor BRAFV600Kgene mutations. In a clinical trial in 322 patients with metastatic or unresectable melanoma with those BRAF mutations, patients receiving trametinib had improvements in PFS and overall survival compared with those receiving chemotherapy. Patients previously treated with other BRAF inhibitors did not appear to benefit from trametinib. Trametinib has been evaluated in combination with other agents. In a phase I/II trial in patients with metastatic melanoma and BRAFV600 mutations, improvement in PFS was seen with the combination of trametinib with the BRAF inhibitor dabrafenib in comparison with dabrafenib alone. The combination of trametinib with gemcitabine did not improve efficacy in patients with metastatic pancreatic cancer regardless of KRAS mutation status. Phase I studies of trametinib in combination with other targeted and conventional chemotherapy agents are ongoing.
Pimasertib showed signs of efficacy in a phase I study, with five patients achieving tumor shrinkage, all with either BRAF or NRAS mutations. In a phase I/II study combining pimasertib with FOLFIRI as a second-line treatment for KRAS-mutated metastatic colorectal cancer, the study could not progress to phase II because effective doses of pimasertib could not be reached because of toxicity. Several phase I and II studies are ongoing combining pimasertib with other targeted agents or conventional chemotherapy for treatment of solid tumors or hematologic malignancies.
Binimetinib (MEK162) has been evaluated in a phase I study in patients with advanced or metastatic biliary cancer or metastatic colorectal cancer. Of the 26 patients with evaluable biliary cancer, one complete response and one partial response were observed. In a phase II study evaluating binimetinib in NRAS-mutated or BRAF-mutated advanced melanoma, objective responses were observed in 20% of patients with NRAS-mutated melanoma and 20% of those with BRAF-mutated melanoma. No responses were reported in patients previously treated with a BRAF inhibitor. A randomized trial comparing binimetinib with chemotherapy in patients with NRAS-mutated melanoma is currently enrolling patients (2014 ASCO Annual Meeting, Abstract TPS9102). Studies evaluating binimetinib in combination with other targeted therapies in melanoma and other solid tumors are ongoing.
Other MEK-inhibiting agents that have completed or are being evaluated in phase I studies include AZD8330 (ARRY-424704), RO4987655 (CH4987655), RO5126766 (a first-in-class dual RAF/MEK inhibitor), WX-554, E6201, and TAK-733.
Despite the prevalence of aberrant RAS/RAF/MEK/ERK signaling in human cancers, the crucial location of MEK1/2 in this pathway, and the availability of highly potent and specific MEK inhibitors, inhibition of MEK has not demonstrated strong therapeutic activity in most early-stage clinical trials. However, promising activity has been demonstrated in combination with BRAF inhibitors. Activity of MEK inhibition in NRAS-mutated tumors also appears promising. Combinations of MEK inhibitors with other targeted agents may also improve efficacy and overcome resistance. However, toxicity of some combinations has been problematic to date. The results of ongoing clinical trials are awaited with interest.
This Fact Sheet was condensed and updated from an editorial by Yujie Zhao, MD, PhD, and Alex A. Adjei, MD, PhD, FACP, published previously in the ASCO Daily News entitled “Exploring the Pathway: Inhibiting MEK for Cancer Therapy.” Dr. Zhao is an assistant professor at Roswell Park Cancer Institute. Dr. Adjei is professor and chair of the Department of Medicine and the Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park Cancer Institute.