Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain.
Health Research Institute of Navarre (IdiSNA), Pamplona, Spain.
Nat Metab. 2023 Sep;5(9):1544-1562. doi: 10.1038/s42255-023-00861-4. Epub 2023 Aug 10.
Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFR neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.
黑色素瘤对靶向治疗和免疫治疗的耐药性与代谢重编程有关。在这里，我们表明，在延长 BRAF 抑制剂（BRAFi）治疗期间，脂肪酸氧化（FAO）的增加导致了小鼠获得性治疗耐药。使用美国食品和药物管理局（FDA）批准和欧洲药品管理局（EMA）批准的抗心绞痛药物雷诺嗪（RANO）靶向 FAO 可延迟获得性 BRAFi 耐药的肿瘤复发。单细胞 RNA 测序分析表明，RANO 减少了具有治疗耐药性的 NGFR 神经嵴干细胞亚群的丰度。此外，通过重排蛋氨酸补救途径，RANO 通过增加抗原呈递和干扰素信号来增强黑色素瘤的免疫原性。RANO 与抗 PD-L1 抗体联合使用可通过增加抗肿瘤免疫反应强烈改善生存。总之，我们表明，RANO 通过其对 FAO 和蛋氨酸补救途径的影响，提高了靶向黑色素瘤治疗的疗效。重要的是，我们的研究表明，RANO 可以使 BRAFi 耐药肿瘤对免疫治疗敏感。由于 RANO 的副作用非常轻微，因此它可能构成一种治疗选择，以改善目前用于治疗转移性黑色素瘤的两种主要策略。
