Clinical Development of BRAF plus MEK Inhibitor Combinations
- PMID: 32540454
- DOI: 10.1016/j.trecan.2020.05.009
Clinical Development of BRAF plus MEK Inhibitor Combinations
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.
Similar articles
-
Metastatic Melanoma Patient-Derived Xenografts Respond to MDM2 Inhibition as a Single Agent or in Combination with BRAF/MEK Inhibition.Clin Cancer Res. 2020 Jul 15;26(14):3803-3818. doi: 10.1158/1078-0432.CCR-19-1895. Epub 2020 Mar 31. Clin Cancer Res. 2020. PMID: 32234759 Free PMC article.
-
Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies.Am J Clin Dermatol. 2021 Jan;22(1):1-10. doi: 10.1007/s40257-020-00572-6. Am J Clin Dermatol. 2021. PMID: 33368052
-
p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):E1600-9. doi: 10.1073/pnas.1404357111. Epub 2014 Apr 7. Proc Natl Acad Sci U S A. 2014. PMID: 24711431 Free PMC article.
-
Targeting BRAF-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy.Oncologist. 2017 Jul;22(7):786-796. doi: 10.1634/theoncologist.2016-0458. Epub 2017 May 9. Oncologist. 2017. PMID: 28487464 Free PMC article. Review.
-
MEK inhibitors for the treatment of non-small cell lung cancer.J Hematol Oncol. 2021 Jan 5;14(1):1. doi: 10.1186/s13045-020-01025-7. J Hematol Oncol. 2021. PMID: 33402199 Free PMC article. Review.
Cited by
-
Wnt/β-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma.Endocrine. 2024 May 28. doi: 10.1007/s12020-024-03887-0. Online ahead of print. Endocrine. 2024. PMID: 38806891
-
Case report: complete long-lasting response to multimodal third line treatment with neurosurgical resection, carmustine wafer implantation and dabrafenib plus trametinib in a BRAFV600E mutated high-grade glioma.Front Oncol. 2024 May 7;14:1359093. doi: 10.3389/fonc.2024.1359093. eCollection 2024. Front Oncol. 2024. PMID: 38774414 Free PMC article.
-
Targeting BRAF pathway in low-grade serous ovarian cancer.J Gynecol Oncol. 2024 Jul;35(4):e104. doi: 10.3802/jgo.2024.35.e104. Epub 2024 May 14. J Gynecol Oncol. 2024. PMID: 38768941 Free PMC article. Review.
-
Unveiling acquired resistance to anti-EGFR therapies in colorectal cancer: a long and winding road.Front Pharmacol. 2024 Apr 22;15:1398419. doi: 10.3389/fphar.2024.1398419. eCollection 2024. Front Pharmacol. 2024. PMID: 38711991 Free PMC article. Review.
-
A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.Adv Ther. 2024 Jul;41(7):2586-2605. doi: 10.1007/s12325-024-02839-4. Epub 2024 May 2. Adv Ther. 2024. PMID: 38698170 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials