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Cited by 20Melanoma and MAPK PathwaysCancer Cells and MetastasisColorectal Cancer Treatments and Studies

Vemurafenib Drives Epithelial-to-Mesenchymal Transition Gene Expression in BRAF Inhibitor‒Resistant BRAFV600E/NRASQ61K Melanoma Enhancing Tumor Growth and Metastasis in a Bioluminescent Murine Model

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Jandova, Jana, Wondrak, Georg T.·2022·Journal of Investigative Dermatology
DOI 10.1016/j.jid.2021.10.007PMC PMC9021323
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Abstract

BRAF inhibitor (BRAFi) resistance compromises long-term survivorship of patients with malignant melanoma, and mutant NRAS is a major mediator of BRAFi resistance. In this study, employing phenotypic and transcriptomic analysis of isogenic melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAF V600E/NRAS Q61 vs. BRAFi-resistant A375-BRAF V600E/NRAS Q61K), we show that BRAFi (vemurafenib) treatment selectively targets BRAF V600E/NRAS Q61K cells upregulating epithelial-to-mesenchymal transition (EMT) gene expression, paradoxically promoting invasiveness and metastasis in vitro and in vivo. First, NanoString nCounter transcriptomic analysis identified the upregulation of specific gene expression networks (EMT and EMT to metastasis) as a function of NRAS Q61K status. Strikingly, BRAFi treatment further exacerbated the upregulation of genes promoting EMT in BRAF V600E/NRAS Q61K cells (with opposing downregulation of EMT-driver genes in the BRAF V600E/NRAS Q61 genotype) as detected by EMT-focused RT 2 Profiler qPCR array analysis. In BRAF V600E/NRAS Q61K cells, BRAFi treatment enhanced proliferation and invasiveness, together with activation of phosphorylated protein kinase B (Ser473), with opposing phenotypic effects observable in BRAF V600E/NRAS Q61 cells displaying downregulation of phosphorylated protein kinase B and phosphorylated extracellular signal-regulated kinase 1/2. In a SCID mouse bioluminescent melanoma metastasis model, BRAFi treatment enhanced lung tumor burden imposed by BRAF V600E/NRAS Q61K cells while blocking BRAF V600E/NRAS Q61 metastasis. These preclinical data document the BRAFi-driven enhancement of tumorigenesis and metastasis in BRAFi-resistant human BRAF V600E/NRAS Q61K melanoma, a finding with potential clinical implications for patients with NRAS-driven BRAFi-resistant tumors receiving BRAFi treatment.

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Cited by

Sorted by citations

Authors
Jandova, J., & Wondrak, G. T.
Affiliations
University of Arizona (US)
Corresponding author
Wondrak, Georg T.
ORCID
Venue
Journal of Investigative Dermatology
Publisher
Elsevier BV
Published
2022-05
Volume
142
Issue
5
Pages
1456-1465.e1
ISSN
0022-202X (ISSN-L)
DOI
10.1016/j.jid.2021.10.007
PMC
PMC9021323
OpenAlex
W3207423345
Cited by
20
References
2
Citations by year
2026: 7 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 1
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Investigative Dermatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (CA023074, 1R01CA229418, ES006694, ES007091)
  • Frederick National Laboratory for Cancer Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
vemurafenib, BRAF inhibitor resistance, BRAF V600E mutation, NRAS Q61K, epithelial-mesenchymal transition, melanoma, metastasis, tumor invasion, Akt, ERK1/2 phosphorylation, gene expression networks, lung metastasis
MeSH terms
Vemurafenib, Animals, Disease Models, Animal, Humans, Melanoma, Membrane Proteins, Mutation, Gene Expression, Mice, SCID, Drug Resistance, Neoplasm, GTP Phosphohydrolases, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Mice

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