Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance
Open accessAbstract
Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)→MEK→ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.
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Discontinuous dosing of the drug could be a strategy to prevent or retard acquired resistance.
“the lessons learned from metronomic treatment strategies for BRAF V600E melanomas as well as EGFR-mutant NSCLCs suggest that discontinuous dosing of the drug could be a strategy to prevent or retard acquired resistance [138, 139].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [138]
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- Authors
- Das Thakur, M., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., & Stuart, D. D.
- Affiliations
- University of California, San Francisco (US)
- University Hospital Zurich (CH)
- Corresponding author
- McMahon, Martin
- Stuart, Darrin D.
- ORCID
- Venue
- Nature
- Published
- 2013-01-09
- Volume
- 494
- Issue
- 7436
- Pages
- 251-255
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3930354
- OpenAlex
- W2058390096
- Cited by
- 730
- References
- 22
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 27 · 2023: 39 · 2022: 35 · 2021: 44 · 2020: 50 · 2019: 66 · 2018: 59 · 2017: 78 · 2016: 69 · 2015: 81 · 2014: 84 · 2013: 66 · 2012: 2
- FWCI
- 44.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007185)
- National Cancer Institute (R01CA176839)
- 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
- vemurafenib resistance, BRAF-mutant melanoma, BRAF V600E mutation, intermittent dosing, drug addiction, MEK/ERK signaling, xenograft models, tumor regression, drug resistance prevention, BRAF inhibitors, treatment durability
- MeSH terms
- Vemurafenib, Animals, Disease Models, Animal, Drug Administration Schedule, Humans, Indoles, Melanoma, Mutation, Neoplasm Transplantation, Sulfonamides, Time Factors, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Subcutaneous Tissue, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice
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