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

Daniela Lulli,Maria Carbone,Saveria Pastore

doi:10.3390/ijms18102227

Abstract

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.

Highlights

Many human cancers contain activating mutations in genes encoding the fundamental signaling cascade constituted of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR), small GTPase Ras (RAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), Raf-1 proto-oncogene (CRAF), and the mitogen-activated protein kinase kinases (MEK) 1 and/or 2 [1]
The identification of activating BRAF mutations in a large number of human tumors led to the development of BRAF-V600E selective inhibitors and the regulatory approval of vemurafenib and dabrafenib [1]
extracellular signal-regulated kinases (ERK) in cells with wild-type BRAF including skin keratinocytes, with consequent high incidence of hyper-proliferative disorders, including squamous cell carcinoma, in patients treated with these drugs [3,4,5]

Summary

Introduction

Many human cancers contain activating mutations in genes encoding the fundamental signaling cascade constituted of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR), small GTPase Ras (RAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), Raf-1 proto-oncogene (CRAF), and the mitogen-activated protein kinase kinases (MEK) 1 and/or 2 [1] These driving oncogenes lead to enhanced dependency on extracellular signal-regulated kinases (ERK) 1 and ERK2 (ERK) signaling and to amplification of ERK-driven cellular processes that are cancer hallmarks, including sustained proliferation, resistance to cell death, activation of invasion, and metastasis [2]. Therapies that associate BRAF inhibitors with MEK inhibitors (dabrafenib with trametinib and vemurafenib with cobimetinib) are the current treatment strategies for BRAF-mutant advanced cancers, including melanoma [11,12]

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