Risk of Selected Dermatological Toxicities in Cancer Patients Treated with
            <i>MEK</i>
            Inhibitors: A Comparative Systematic Review and Meta-Analysis

Abdel‐Rahman, Omar; Elhalawani, Hesham; Ahmed, Hoda; Ellithy, Mahmoud

doi:10.2217/fon.15.265

Cited by 18 publications

(15 citation statements)

References 41 publications

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“…The therapeutic use of kinase inhibitors and biological agents targeting kinase signaling pathways has introduced new toxicities in oncology clinics [ 5 ]. In particular, treatments that include EGFR inhibitors or MEK inhibitors typically associate with an increased risk of all-grade inflammatory skin rash characterized by papulo-pustular eruptions and acneiform dermatitis [ 13 , 14 ]. In our search for the molecular mechanisms underlying the pro-inflammatory and cytotoxic potential of EGFR inhibitors in the skin, we recently documented drug-induced activation of a type I interferon (IFN) innate immune response, with enhanced expression of the keratinocyte-specific IFN-κ, a number of anti-viral effectors including distinct members of the interferon-induced tetratricopeptide repeats (IFIT) family and immune mediators [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes

Lulli

Carbone

Pastore

2017

IJMS

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Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash. Here, we investigated the response of normal human keratinocytes to the MEK inhibitors trametinib and cobimetinib, alone and in combination with the v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors dabrafenib and vemurafenib, in terms of signal transduction and de novo gene expression. MEK inhibitors triggered enhanced expression of interferon regulatory factor 1 (IRF1) and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and up-regulated the keratinocyte-specific type I interferon κ (IFN-κ), the anti-viral effectors interferon-induced tetratricopeptide repeats (IFIT) 1 and 2, and the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) and the C-X-C motif chemokine 10 (CXCL10), both at the mRNA and protein level. Impairment of IRF1 expression, or abrogation of STAT1 phosphorylation due to IFN-κ gene silencing, suppressed anti-viral and pro-inflammatory gene expression. These data suggest that, similar to what we observed for epidermal growth factor receptor (EGFR) blockade, MEK inhibition activates a type I interferon response, which is now recognized as an effective anti-cancer response, in human epidermal keratinocytes.

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Section: Introductionmentioning

confidence: 99%

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes

Lulli

Carbone

Pastore

2017

IJMS

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“… 1 , 2 , 3 One review of 14 trials of cancer patients on 3 MEK inhibitors reported the relative risk of acneiform dermatitis at 8.44 (95% confidence interval, 2.39-29.81; P = .0009). 4 This eruption does not always respond to traditional acne therapy with topical treatment and oral antibiotics. 2 Skin toxicities are considered an important cause for treatment interruption of MEK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Isotretinoin for the treatment of severe acneiform eruptions associated with the MEK inhibitor trametinib

et al. 2020

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“…Regardless of such improvements, MEK inhibitors have been associated with serious cytotoxicity [10,11]. …”

Section: Discussionmentioning

confidence: 99%

“…Treatment with MEK inhibitors can lead to serious iatrogenic responses [10,11]. Ocular toxicity seems to be associated with MEK inhibitors [12].…”

Section: Introductionmentioning

confidence: 99%

Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis

et al. 2016

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Objectives: This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. Methods: A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I² statistics. Results: Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p < 0.0001; I² = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p < 0.0001; I² = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p < 0.0001; I² = 0%), and blurred vision (OR 2.30; 95% CI 1.50-3.54; p < 0.0001; I² = 60.1%), but not for uveitis (OR 0.99; 95% CI 0.14-7.03; p = 0.991; I² = 2.9%) or eye haemorrhage (OR 0.72; 95% CI 0.04-12.39; p = 0.824; I² = 29.8%). Conclusions: Treatment with MEK inhibitors seems to increase the risk of ophthalmic adverse effects. A need for monitoring the safety of this class of drugs exists. Regulators, clinicians, and other health care professionals must, together, be involved in this process.

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Risk of Selected Dermatological Toxicities in Cancer Patients Treated with MEK Inhibitors: A Comparative Systematic Review and Meta-Analysis

Abstract: Our meta-analysis has demonstrated that MEK inhibitor-based treatment is associated with an increased risk of all-grade and high-grade skin rash and acneiform dermatitis compared with control.

Cited by 18 publications

References 41 publications

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes

The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes

Isotretinoin for the treatment of severe acneiform eruptions associated with the MEK inhibitor trametinib

Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis

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