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

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...

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Autores principales: Lulli, Daniela, Carbone, Maria Luigia, Pastore, Saveria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666906/
https://www.ncbi.nlm.nih.gov/pubmed/29064427
http://dx.doi.org/10.3390/ijms18102227
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author Lulli, Daniela
Carbone, Maria Luigia
Pastore, Saveria
author_facet Lulli, Daniela
Carbone, Maria Luigia
Pastore, Saveria
author_sort Lulli, Daniela
collection PubMed
description 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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spelling pubmed-56669062017-11-09 The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes Lulli, Daniela Carbone, Maria Luigia Pastore, Saveria Int J Mol Sci Article 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. MDPI 2017-10-24 /pmc/articles/PMC5666906/ /pubmed/29064427 http://dx.doi.org/10.3390/ijms18102227 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lulli, Daniela
Carbone, Maria Luigia
Pastore, Saveria
The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes
title The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes
title_full The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes
title_fullStr The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes
title_full_unstemmed The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes
title_short The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes
title_sort mek inhibitors trametinib and cobimetinib induce a type i interferon response in human keratinocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666906/
https://www.ncbi.nlm.nih.gov/pubmed/29064427
http://dx.doi.org/10.3390/ijms18102227
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