Journal
CELL REPORTS
Volume 33, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108421
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Funding
- Sebastien Bazin
- Fondation Carrefour
- INSERM
- CNRS
- Gustave Roussy
- Fondation ARC pour la Recherche sur le Cancer [PJA20161204588]
- Institut National Du Cancer [2013-1-MEL-01-ICR-1]
- Collectif Ensemble contre le melanome
- Association Vaincre le Melanome
- Les Sites de recherche Integres sur le Cancer (SIRIC) label Gustave Roussy
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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 beta-oxidation (FAO) that is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). 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 PPAR alpha correlates with patients' outcomes. These results pave the way for a metabolic strategy to overcome drug resistance.
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