Targeting the ERK Signaling Pathway in Melanoma

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabraf...

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Bibliographic Details
Published in:International journal of molecular sciences 2019-03, Vol.20 (6), p.1483
Main Authors: Savoia, Paola, Fava, Paolo, Casoni, Filippo, Cremona, Ottavio
Format: Article
Language:English
Subjects:
BRAF inhibitors
Cancer
ERK inhibitors
ERK pathway
Kinases
MEK inhibitors
Melanoma
melanoma treatment
metastatic melanoma
Mutation
NRAS inhibitors
Review
target therapy
Tumors
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Summary:The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms20061483