open access

Vol 69, No 3-4 (2019)
Review articles
Published online: 2019-10-31
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Mechanisms of melanoma resistance to treatment with BRAF and MEK inhibitors

Ewa Bartnik, Michał Fiedorowicz, Anna M. Czarnecka
DOI: 10.5603/NJO.2019.0025
·
Nowotwory. Journal of Oncology 2019;69(3-4):133-141.

open access

Vol 69, No 3-4 (2019)
Review articles
Published online: 2019-10-31

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.

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Keywords

BRAF; MEK; melanoma; MAPK; drug resistance

About this article
Title

Mechanisms of melanoma resistance to treatment with BRAF and MEK inhibitors

Journal

Nowotwory. Journal of Oncology

Issue

Vol 69, No 3-4 (2019)

Pages

133-141

Published online

2019-10-31

DOI

10.5603/NJO.2019.0025

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

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