Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation

• Published in: Cell reports (Cambridge) 2020-11, Vol.33 (8), p.108421-108421, Article 108421
• Main Authors: Shen, Shensi, Faouzi, Sara, Souquere, Sylvie, Roy, Severine, Routier, Emilie, Libenciuc, Cristina, André, Fabrice, Pierron, Gérard, Scoazec, Jean-Yves, Robert, Caroline
• Format: Article
• Language: English
• Subjects: 3-Hydroxyacyl CoA Dehydrogenases - metabolism; Acetyl-CoA C-Acyltransferase - metabolism; Acyl-CoA Oxidase - metabolism; Animals; Carbon-Carbon Double Bond Isomerases - metabolism; Enoyl-CoA Hydratase - metabolism; fatty acid oxidation; Humans; Life Sciences; melanoma; Melanoma - genetics; Melanoma - pathology; Mice; peroxisome; persistent cancer cell; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Racemases and Epimerases - metabolism; targeted therapy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108421

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 β-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. [Display omitted] •Melanoma persister cells switch from glycolysis to mitochondrial respiration•Fatty acid oxidation (FAO) signature is upregulated in melanoma persister cells•Peroxisomal FAO is mediated by PPARα-ACOX1 axis in persister cells•Peroxisomal FAO inhibition delays the emergence of resistance to targeted therapy Drug resistance can originate from non-genetic cancer persister cells. Shen et al. discover that peroxisomal lipid metabolism is an “Achilles heel” of melanoma persister cells. Inhibition of this metabolic adaptation significantly improves the efficacy of melanoma-targeted therapy.