Vemurafenib resistance reprograms melanoma cells towards glutamine dependence
Open accessAbstract
BACKGROUND: (V600) BRAF mutations drive approximately 50% of metastatic melanoma which can be therapeutically targeted by BRAF inhibitors (BRAFi) and, based on resistance mechanisms, the combination of BRAF and MEK inhibitors (BRAFi + MEKi). Although the combination therapy has been shown to provide superior clinical benefits, acquired resistance is still prevalent and limits the overall survival benefits. Recent work has shown that oncogenic changes can lead to alterations in tumor cell metabolism rendering cells addicted to nutrients, such as the amino acid glutamine. Here, we evaluated whether melanoma cells with acquired resistance display glutamine dependence and whether glutamine metabolism can be a potential molecular target to treat resistant cells. METHODS: Isogenic BRAFi sensitive parental (V600) BRAF mutant melanoma cell lines and resistant (derived by chronic treatment with vemurafenib) sub-lines were used to assess differences in the glutamine uptake and sensitivity to glutamine deprivation. To evaluate a broader range of resistance mechanisms, isogenic pairs where the sub-lines were resistant to BRAFi + MEKi were also studied. Since resistant cells demonstrated increased sensitivity to glutamine deficiency, we used glutaminase inhibitors BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide] and L-L-DON (6-Diazo-5-oxo-L-norleucine) to treat MAPK pathway inhibitor (MAPKi) resistant cell populations both in vitro and in vivo. RESULTS: We demonstrated that MAPKi-acquired resistant cells uptook greater amounts of glutamine and have increased sensitivity to glutamine deprivation than their MAPKi-sensitive counterparts. In addition, it was found that both BPTES and L-DON were more effective at decreasing cell survival of MAPKi-resistant sub-lines than parental cell populations in vitro. We also showed that mutant NRAS was critical for glutamine addiction in mutant NRAS driven resistance. When tested in vivo, we found that xenografts derived from resistant cells were more sensitive to BPTES or L-DON treatment than those derived from parental cells. CONCLUSION: Our study is a proof-of-concept for the potential of targeting glutamine metabolism as an alternative strategy to suppress acquired MAPKi-resistance in melanoma.
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Targeting glutamine metabolism suppresses acquired resistance to MAPK inhibitors in melanoma cells.
“Thinking more broadly about the interplay of metabolism with RAS signaling, targeting glutamine metabolism has also been found to suppress acquired resistance to MAPK inhibitors in melanoma cells72.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [72]
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- Authors
- Hernandez-Davies, J. E., Tran, T. Q., Reid, M. A., Rosales, K. R., Lowman, X. H., Pan, M., Moriceau, G., Yang, Y., Wu, J., Lo, R. S., & Kong, M.
- Affiliations
- City Of Hope National Medical Center (US)
- University of California, Los Angeles (US)
- Corresponding author
- Kong, Mei
- Venue
- Journal of Translational Medicine
- Published
- 2015-07-03
- Volume
- 13
- Issue
- 1
- Pages
- 210-210
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC4490757
- OpenAlex
- W1640505003
- Cited by
- 131
- References
- 33
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 1 · 2023: 13 · 2022: 16 · 2021: 28 · 2020: 12 · 2019: 12 · 2018: 12 · 2017: 11 · 2016: 14 · 2015: 2
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Ralph M. Parsons Foundation
- V Foundation for Cancer Research
- Hope Center for Neurological Disorders
- National Institutes of Health
- National Cancer Institute (R01CA183989)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- vemurafenib resistance, melanoma, glutamine addiction, glutamine metabolism, BRAF V600 mutation, MEK inhibitors, MAPK pathway inhibitors, glutaminase inhibitors, BPTES, NRAS mutation, cancer metabolism, glutamine deprivation, acquired drug resistance
- MeSH terms
- Vemurafenib, Animals, Enzyme Inhibitors, Glutaminase, Glutamine, Humans, Indoles, Melanoma, Membrane Proteins, Sulfonamides, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, GTP Phosphohydrolases, Cell Line, Tumor, Gene Knockdown Techniques, Cellular Reprogramming
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