罗纳素诱导的代谢重新连接改善了黑色素瘤对向治疗和免疫治疗的反应
Marta Redondo-Muñoz1,2, Francisco Javier Rodriguez-Baena3, Paula Aldaz1,2
1Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain.
Nature metabolism
|August 10, 2023
概括
抗腹痛药物兰诺 (RANO) 针对脂肪酸氧化 (FAO) 克服黑色素瘤对BRAF抑制剂 (BRAFi) 的抵抗. 拉诺还通过重新连接 metionin 救援途径来增强免疫疗法,改善患者的生存率.
科学领域:
- 在瘤学瘤学.
- 代谢途径 代谢途径
- 免疫治疗是一种免疫疗法.
背景情况:
- 黑色素瘤对向治疗和免疫治疗的耐药性是一个重大的临床挑战.
- 代谢的重新连接,特别是脂肪酸氧化 (FAO) 的增加,与对BRAF抑制剂 (BRAFi) 的获得性耐药性有关.
研究的目的:
- 调查粮农组织在黑色素瘤中BRAFi耐药性的作用.
- 为了评估粮农组织对 ranolazine (RANO) 的向治疗在克服黑色素瘤治疗耐药性的有效性.
- 探索RANO对黑色素瘤免疫性的影响及其在组合治疗中的潜力.
主要方法:
- 在体内的黑色素瘤小鼠模型与获得的BRAFi耐药性.
- 单细胞RNA测序用于分析细胞亚群.
- 评估新陈代谢途径,包括粮农组织和氨酸救援途径.
- 使用RANO和抗PD-L1抗体进行组合治疗的研究.
主要成果:
- 增加的FAO有助于在黑色素瘤中获得对BRAFi的耐药性.
- 兰诺 (RANO) 治疗通过向粮农组织,延迟了瘤复发在获得了BRAFi耐药性的小鼠.
- 拉诺降低了耐治疗NGFRhi神经干细胞亚种群的丰富性.
- RANO重新连接 metionin 救援途径,通过增加抗原呈现和干扰素信号传递来增强黑色素瘤免疫性.
- 将RANO与抗PD-L1抗体相结合,通过增强抗瘤免疫反应,显著改善了生存率.
结论:
- 兰诺 (RANO) 通过抑制FAO和调节氨酸救援途径来提高向黑色素瘤治疗的疗效.
- 拉诺显示有可能使BRAFi抗性黑色素瘤对免疫疗法的敏感.
- 随着有利的副作用概况,RANO可能为改善当前转移性黑色素瘤治疗策略提供治疗选择.
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