Abstract
Melanoma onset and progression are associated with a high variety of activating mutations in the MAPK-pathway, most frequently involving BRAF (35-45%) and NRAS (15-25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed.
Keywords:
BRAF; Immunotherapy; MEK; Mechanisms of resistance; Melanoma; Target therapy.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Clinical Trials as Topic
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Disease Progression
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Epigenesis, Genetic / drug effects
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Gain of Function Mutation
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / genetics
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Melanoma / drug therapy*
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Melanoma / genetics
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Melanoma / pathology
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MicroRNAs / metabolism
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Molecular Targeted Therapy / methods
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Phosphatidylinositol 3-Kinase / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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TOR Serine-Threonine Kinases / metabolism
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Treatment Outcome
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / genetics
Substances
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Antineoplastic Agents
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MicroRNAs
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Protein Kinase Inhibitors
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MTOR protein, human
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Phosphatidylinositol 3-Kinase
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases