ArticleJournal of experimental & clinical cancer research : CR2024
Augmenting MEK inhibitor efficacy in BRAF wild-type melanoma: synergistic effects of disulfiram combination therapy.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Balancing between cuproplasia and copper-dependent cell death: molecular basis and clinical implications of ATOX1 in cancer.Journal of experimental & clinical cancer research : CR · 2025Review
- Copper-mediated SEC14L3 promotes cuproptosis to inhibit hepatocellular carcinoma growth via ERK/YY1/FDX1 axis.Communications biology · 2025Article
- GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- EGFR influences the resistance to targeted therapy in BRAFArchives of dermatological research · 2025Article
- Article
- Current Insights into the Role of UV Radiation-Induced Oxidative Stress in Melanoma Pathogenesis.International journal of molecular sciences · 2024Review
- Exploring the In Vitro and In Vivo Therapeutic Potential of BRAF and MEK Inhibitor Combination in NRAS-Mutated Melanoma.Cancers · 2023Article
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundMEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib.
methodsThe effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi.
resultsDiethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib.
conclusionsDisulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma.
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