Melanoma Persister Cells are Tolerant to BRAF/MEK Inhibitors Via ACOX1-Mediated Fatty Acid Oxidation

Emerging evidences indicate 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 PPARα. Knockdown of the key peroxisomal FAO enzyme, ACOX1, as well as treatment with the peroxisomal FAO inhibitor thioridazine specifically suppresses the oxidative respiration of persister cells and significantly decreased their emergence. Consistently, 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 correlate with patients’ outcomes. These results pave the way for a new metabolic strategy to overcome drug resistance.