Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation.
Cell Rep
; 33(8): 108421, 2020 11 24.
Article
em En
| MEDLINE
| ID: mdl-33238129
ABSTRACT
Emerging evidence indicates that non-mutational drug tolerance mechanisms underlie the survival of residual cancer "persister" cells. Here, we find that BRAF(V600E) mutant melanoma persister cells tolerant to BRAF/MEK inhibitors switch their metabolism from glycolysis to oxidative respiration supported by peroxisomal fatty acid ß-oxidation (FAO) that is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARα). Knockdown of the key peroxisomal FAO enzyme, acyl-CoA oxidase 1 (ACOX1), as well as treatment with the peroxisomal FAO inhibitor thioridazine, specifically suppresses the oxidative respiration of persister cells and significantly decreases their emergence. Consistently, a combination treatment of BRAF/MEK inhibitors with thioridazine in human-melanoma-bearing mice results in a durable anti-tumor response. In BRAF(V600E) melanoma samples from patients treated with BRAF/MEK inhibitors, higher baseline expression of FAO-related genes and PPARα correlates with patients' outcomes. These results pave the way for a metabolic strategy to overcome drug resistance.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acetil-CoA C-Aciltransferase
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Isomerases de Ligação Dupla Carbono-Carbono
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Racemases e Epimerases
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Acil-CoA Oxidase
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Proteínas Proto-Oncogênicas B-raf
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Inibidores de Proteínas Quinases
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Enoil-CoA Hidratase
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3-Hidroxiacil-CoA Desidrogenases
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Melanoma
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article