Abstract
Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.
Keywords:
BRAF V600 mutation; BRAF inhibitor; MEK inhibitor; anaplastic thyroid cancer; melanoma; non-small cell lung cancer.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / mortality
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Proliferation / genetics
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Clinical Trials as Topic / statistics & numerical data
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Drug-Related Side Effects and Adverse Reactions / epidemiology
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Drug-Related Side Effects and Adverse Reactions / etiology
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Drug-Related Side Effects and Adverse Reactions / prevention & control
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Humans
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Incidence
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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MAP Kinase Signaling System / drug effects
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Melanoma / drug therapy
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Melanoma / genetics
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Melanoma / mortality
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Melanoma / pathology
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Mice
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mutation
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Progression-Free Survival
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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 B-raf / metabolism
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics
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Skin Neoplasms / mortality
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Skin Neoplasms / pathology
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Thyroid Carcinoma, Anaplastic / drug therapy
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Thyroid Carcinoma, Anaplastic / genetics
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Thyroid Carcinoma, Anaplastic / mortality
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Thyroid Carcinoma, Anaplastic / pathology
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Thyroid Neoplasms / drug therapy
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / mortality
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Thyroid Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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Protein Kinase Inhibitors
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Mitogen-Activated Protein Kinase Kinases