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Mechanisms of melanoma resistance to treatment with BRAF and MEK inhibitors
Affiliations- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Poland
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute — Oncology Center, Warsaw, Poland
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Abstract
Several mechanisms of resistance to inhibition of BRAF activity in melanoma cells have been described so far. Genetic studies have shown that mutations in MEK1 kinase (MAP kinase kinase), which result in constitutive activation of ERK kinase, result in resistance to treatment. Another mechanism of the acquired BRAF inhibition resistance is the accumulation of activating mutations in the NRAS oncogene, which drives the activation of CRAF. This in turn leads to a permanent activation of the signal transduction to MEK and ERK. Another important mechanism of resistance is the formation of variants of the BRAF V600E gene splicing, including variants that lack exons 4 to 8 containing the RAS-binding domain. The presence of the p61 BRAF V600E variant leads to the constitutive ERK signal, which is resistant to RAF inhibition. In addition, treatment resistance is affected by hyperactivation of tyrosine kinase receptors such as platelet-derived factor receptor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and erythropoietin-producing hepatocellular receptors (EPH) – leading to the induction of the 3-phosphoinositol kinase pathway (PI3K) in patients treated with BRAF or MEK inhibitors. Another interesting path of BRAFi/MEKi resistance is over-expression of the epidermal growth factor receptor (EGFR) through negative feedback in patients treated with BRAF inhibitors (BRAFi) – EGFR is not normally expressed in untreated melanomas.
Abstract
Several mechanisms of resistance to inhibition of BRAF activity in melanoma cells have been described so far. Genetic studies have shown that mutations in MEK1 kinase (MAP kinase kinase), which result in constitutive activation of ERK kinase, result in resistance to treatment. Another mechanism of the acquired BRAF inhibition resistance is the accumulation of activating mutations in the NRAS oncogene, which drives the activation of CRAF. This in turn leads to a permanent activation of the signal transduction to MEK and ERK. Another important mechanism of resistance is the formation of variants of the BRAF V600E gene splicing, including variants that lack exons 4 to 8 containing the RAS-binding domain. The presence of the p61 BRAF V600E variant leads to the constitutive ERK signal, which is resistant to RAF inhibition. In addition, treatment resistance is affected by hyperactivation of tyrosine kinase receptors such as platelet-derived factor receptor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and erythropoietin-producing hepatocellular receptors (EPH) – leading to the induction of the 3-phosphoinositol kinase pathway (PI3K) in patients treated with BRAF or MEK inhibitors. Another interesting path of BRAFi/MEKi resistance is over-expression of the epidermal growth factor receptor (EGFR) through negative feedback in patients treated with BRAF inhibitors (BRAFi) – EGFR is not normally expressed in untreated melanomas.
Keywords
BRAF; MEK; melanoma; MAPK; drug resistance
About this articleTitle
Mechanisms of melanoma resistance to treatment with BRAF and MEK inhibitors
Journal
Nowotwory. Journal of Oncology
Issue
Article type
Review paper
Pages
133-141
Published online
2019-10-31
Page views
651
Article views/downloads
899
DOI
Bibliographic record
Nowotwory. Journal of Oncology 2019;69(3-4):133-141.
Keywords
BRAF
MEK
melanoma
MAPK
drug resistance
Authors
Ewa Bartnik
Michał Fiedorowicz
Anna M. Czarnecka