INSERM U981, Villejuif, France; Gustave Roussy Cancer Campus, Villejuif, France.
Université Paris-Saclay, Kremlin-Bicêtre, France; Dermato-Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
Cell Rep. 2020 Nov 24;33(8):108421. 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.
新出现的证据表明，非突变性药物耐受机制是残留癌症“持久细胞”存活的基础。在这里，我们发现，对 BRAF/MEK 抑制剂具有耐受性的 BRAF(V600E)突变黑色素瘤持久细胞将其代谢从糖酵解切换为过氧化物酶体脂肪酸 β-氧化（FAO）支持的氧化呼吸，而过氧化物酶体增殖物激活受体 α（PPARα）转录调控。关键过氧化物酶体 FAO 酶酰基辅酶 A 氧化酶 1（ACOX1）的敲低，以及过氧化物酶体 FAO 抑制剂噻氯匹定的治疗，特异性地抑制持久细胞的氧化呼吸，并显著降低其出现。一致地，BRAF/MEK 抑制剂与噻氯匹定联合治疗荷有人黑色素瘤的小鼠可导致持久的抗肿瘤反应。在接受 BRAF/MEK 抑制剂治疗的患者的 BRAF(V600E)黑色素瘤样本中，FAO 相关基因和 PPARα 的基线表达较高与患者的结局相关。这些结果为克服耐药性的代谢策略铺平了道路。
