Aberrant activation of the RAS–RAF–MEK–ERK pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1 and MEK2 have crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis. Highly selective and potent MEK inhibitors have been developed and assessed in numerous clinical studies. However, only hints of antitumour activity have been seen in tumours other than melanoma. In an article published in July 2014 issue of the Nature Reviews Clinical Oncology, Drs Yujie Zhao and Alex Adjei of the Roswell Park Cancer Institute in Buffalo, NY, USA review MEK1/2 signalling, activity of MEK inhibitors and common toxic effects.
As single-agent, these inhibitors, in general, possess a narrow spectrum of activity, with the most pronounced activities being observed in patients with BRAF-mutant and NRAS-mutant melanoma and potentially other types of tumour harbouring these mutations, although hints of activity in biliary cancers, serous ovarian cancer, and uveal melanoma have been observed. The only approved indication for MEK inhibitors to date is trametinib alone or in combination with dabrafenib for the treatment of BRAF V600E/K-mutation-positive unresectable or metastatic melanoma.
In their article, the authors review characteristics of next MEK inhibitors: PD0325901, selumetinib, cobimetinib, refametinib, trametinib, pimasertib, MEK162, AZD8330, RO4987655, RO5126766, WX-554, E6201, GDC-0623 and TAK-733. They discuss the clinical experience with MEK inhibitors and consider the novel approaches to MEK-inhibition therapy.
Common toxic effects of MEK inhibitors
In general, MEK inhibitors are well tolerated. In addition to toxic effects common to small-molecule kinase inhibitors—such as rash, fatigue, and diarrhoea—toxicity events unique to MEK inhibitors, specifically ocular toxic effects that manifest as blurred vision and loss of visual acuity, have been described.
Although retinal vein occlusion has been observed in rare cases, the most frequent underlying pathology for visual changes associated with the use of MEK inhibitors is central serous retinopathy. Unlike retinal vein occlusion, which is a potentially serious toxicity that can result in permanent loss of vision, central serous retinopathy usually resolves spontaneously after interruption of treatment.
Peripheral oedema, particularly periorbital oedema, and markedly elevated serum levels of creatine phosphokinase (CPK) without troponin abnormalities or any identifiable underlying pathology (such as rhabdomyolysis) have been observed after MEK-inhibitor therapy.
Dropped-head syndrome, an uncommon progressive weakness of neck extensor muscles that is characterised by focal non-inflammatory myopathy, moderately elevated serum CPK levels, lack of response to corticosteroids, and resolution after discontinuation of the agent, has been reported in patients exposed to MEK inhibitors.
However, reduction in the frequency of BRAF-inhibitor-associated cutaneous squamous cell carcinoma detected after combined treatment with BRAF and MEK inhibitors represents a rare situation in which combination therapy exhibits fewer off-target adverse effects than single-agent therapy.
Rare cases of left ventricular dysfunction have been reported after therapy with MEK inhibitors, as have central nervous system (CNS) effects, including hallucinations and confusion, presumably attributable to a subset of MEK-targeted agents with good CNS penetration. Although evidence of blood–brain barrier penetration suggests that at least some MEK inhibitors can enter the CNS and thus might be active against brain metastases, this hypothesis has not been confirmed in patients treated with such agents.
Future directions
Combination therapies represent a potential approach for overcoming the complexities of the RAS–RAF–MEK–MAPK pathway that are associated with resistance to RAF and MEK inhibition, and potentiating the activity of other antitumour agents by simultaneous inhibition of the Ras–RAF–MEK–MAPK pathway.
A number of combination therapies incorporating MEK inhibitors are being tested in clinical trials, but such therapeutic approaches have been hampered by toxicity issues, which prevent the use of adequate doses of MEK inhibitors. Alternate administration schedules, such as intermittent dosing, which could completely shut down the RAS–RAF–MEK–MAPK pathway while enabling recovery of normal tissues, might enhance the efficacy of MEK-inhibitor-based therapies. In particular, dual inhibition of MEK and RAF kinases offers advantages regarding both increased efficacy and reduced toxicity, and is a promising therapeutic strategy in targeting the RAS–RAF–MEK–MAPK pathway.
Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors. However, other than NRAS and BRAF V600 mutations, no biomarkers have demonstrated a consistent correlation with treatment response after MEK inhibition.
Reference
Zhao Y, Adjei A. The clinical development of MEK inhibitors. Nat Rev Clin Oncol 2014; 11(7): 385–400. doi:10.1038/nrclinonc.2014.83