ArticleCell death & disease2018
Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors.
Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 2 of them syntheses that pooled it.
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Who cites it
58 citing papers in PubMed, 2 syntheses or guidelines pooled it, 82 citations in OpenAlex.
- Research progress of Chinese medicinal monomers in the process of melanoma occurrence.Pharmaceutical biology · 2025Pooled it
- The dual role of Nrf2 in melanoma: a systematic review.BMC molecular and cell biology · 2023Pooled it
- MAPK Inhibitor-Tolerant Persister Cells in Melanoma: Mechanisms and Therapeutic Vulnerabilities.Cancer science · 2026Review
- A Hypoxia-Apoptosis Stress-Adaptation State Defines Immune-Low Melanoma and Predicts Metastatic Risk.Cancers · 2026Article
- TET2 downregulation limits oxidative stress-induced cytotoxicity of high dose ascorbate in dabrafenib-resistant melanoma cells.Cancer drug resistance (Alhambra, Calif.) · 2026Article
- Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.International journal of molecular sciences · 2025Article
- NRF2 activation in cancer and overview of NRF2 small molecule inhibitors.Archives of pharmacal research · 2025Review
- Metabolic reprogramming in melanoma therapy.Cell death discovery · 2025Review
- Iron, copper and disulfide dysregulation: molecular crossroads of metabolic cell death in melanoma progression.Frontiers in pharmacology · 2025Review
- The Role of Glucose-6-Phosphate Dehydrogenase in Skin Cancer Metabolism: A Paradigm Shift in Treatment Approaches.Cancers · 2024Review
- Oxidative State in Cutaneous Melanoma Progression: A Question of Balance.Antioxidants (Basel, Switzerland) · 2024Review
- Modifications of Nanobubble Therapy for Cancer Treatment.International journal of molecular sciences · 2024Review
- Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.Annals of hematology · 2024Article
- The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors.Cancer cell international · 2024Article
- Melanoma biology and treatment: a review of novel regulated cell death-based approaches.Cancer cell international · 2024Review
- Metabolic Profiling to Assess Response to Targeted and Immune Therapy in Melanoma.International journal of molecular sciences · 2024Review
- Redox pathways in melanoma.Advances in cancer research · 2024Review
- Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma.Pharmacological research · 2023Article
- Skewing cPLAScience signaling · 2023Article
- Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma.Antioxidants (Basel, Switzerland) · 2023Article
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc-amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.
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