ArticleCancer & metabolism2022
Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.
Article in Cancer & metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 26 citations in OpenAlex.
- Drug development targeting the mitochondrial respiratory chain of Sparganum proliferum: Initial biochemical and drug discovery insights into the enigmatic helminth parasite.PLoS neglected tropical diseases · 2026Article
- Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study.BMC cancer · 2024Article
- Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.Molecular cell · 2024Article
- Unveiling ferroptosis: a new frontier in skin disease research.Frontiers in immunology · 2024Review
- Causal effects of lipid-lowering drugs on skin diseases: a two-sample Mendelian randomization study.Frontiers in medicine · 2024Article
- Metabolic protein kinase signalling in neuroblastoma.Molecular metabolism · 2023Review
- A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC-OXPHOS axis.Journal of translational medicine · 2023Article
- Metabolic modelling-based in silico drug target prediction identifies six novel repurposable drugs for melanoma.Cell death & disease · 2023Article
- Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy.Medicina (Kaunas, Lithuania) · 2022Review
- Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity.Cancer & metabolism · 2022Article
- Proteomics as a tool to improve novel insights into skin diseases: what we know and where we should be going.Frontiers in surgery · 2022Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundPrimary and posttreatment resistance to BRAF
methodsWe performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment.
resultsA combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation.
conclusionsSTN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.
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