Diverse Mechanisms of BRAF Inhibitor Resistance in Melanoma Identified in Clinical and Preclinical Studies
Open accessAbstract
BRAF inhibitor therapy may provide profound initial tumor regression in metastatic melanoma with BRAF V600 mutations, but treatment resistance often leads to disease progression. A multi-center analysis of BRAF inhibitor resistant patient tissue samples detected genomic changes after disease progression including multiple secondary mutations in the MAPK/Erk signaling pathway, mutant BRAF copy number gains, and BRAF alternative splicing as the predominant putative mechanisms of resistance, but 41.7% of samples had no known resistance drivers. In vitro models of BRAF inhibitor resistance have been developed under a wide variety of experimental conditions to investigate unknown drivers of resistance. Several in vitro models developed genetic alterations observed in patient tissue, but others modulate the response to BRAF inhibitors through increased expression of receptor tyrosine kinases. Both secondary genetic alterations and expression changes in receptor tyrosine kinases may increase activation of MAPK/Erk signaling in the presence of BRAF inhibitors as well as activate PI3K/Akt signaling to support continued growth. Melanoma cells that develop resistance in vitro may have increased dependence on serine or glutamine metabolism and have increased cell motility and metastatic capacity. Future studies of BRAF inhibitor resistance in vitro would benefit from adhering to experimental parameters that reflect development of BRAF inhibitor resistance in patients through using multiple cell lines, fully characterizing the dosing strategy, and reporting the fold change in drug sensitivity.
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Resistance to BRAF inhibitors in melanoma has been associated with an increase in metastasis and disease progression.
“Resistance to BRAF inhibitors in melanoma has been associated with an increase in metastasis and disease progression [43].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [43]
The Abstract says BRAF inhibitor resistance often leads to disease progression. The section on phenotypic changes in resistant cell lines reports increased metastatic capacity, but it does not establish an increase in actual metastasis among patients. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAcquired resistance will invariably occur after prolonged treatment with targeted drugs, including RAF and MEK inhibitors.
“It has been long recognized that acquired resistance will invariably occur after prolonged treatment with targeted drugs, including those against Ras downstream effectors, such as RAF and MEK.72, 73, 74”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [72]
Prolonged treatment with either RAF or MEK inhibitors results in rebounded ERK activation due to amplification of upstream drivers such as RTKs and Ras.
“For example, prolonged treatment of either RAF or MEK inhibitors results in rebounded ERK activation due to the amplification of upstream drivers, such as RTKs and Ras.72,74”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [72]
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“Resistance to BRAF inhibitors in melanoma has been associated with an increase in metastasis and disease progression [43].”
- Authors
- Luebker, S. A., & Koepsell, S. A.
- Affiliations
- University of Nebraska Medical Center (US)
- Corresponding author
- Luebker, Stephen A.
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2019-04-17
- Volume
- 9
- Pages
- 268-268
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC6478763
- OpenAlex
- W2938062190
- Cited by
- 194
- References
- 62
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 25 · 2023: 32 · 2022: 27 · 2021: 41 · 2020: 30 · 2019: 3
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Nebraska Medical Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- BRAF inhibitor resistance, melanoma, BRAF V600 mutation, ERK signaling, secondary mutations, receptor tyrosine kinase, PI3K/Akt signaling, serine metabolism, glutamine metabolism, cell motility, metastasis, drug sensitivity
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