扰乱YAP1介导的谷氨胺代谢会诱导合成致死性,同时在骨髓瘤中抑制ODC1
Hongsheng Wang1,2, Yining Tao1,2, Jing Han1,2
1Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China.
Cellular oncology (Dordrecht, Netherlands)
|August 8, 2024
概括
这项研究表明,向YAP1介导的谷氨酸代谢途径可以克服骨髓瘤 (OS) 中的耐药性. 将DFMO与像CIL56这样的YAP1抑制剂结合起来,为转移性和复发性OS提供了一个有希望的治疗策略.
科学领域:
- 在瘤学瘤学.
- 代谢途径 代谢途径
- 癌症治疗治疗 癌症治疗
背景情况:
- 骨髓瘤 (OS) 是一种常见于青少年的恶性骨瘤,经常发展出化学疗法耐药性和转移.
- 对于复发性和转移性OS存在有限的治疗选择,需要新的治疗点.
研究的目的:
- 确定转移性和复发性骨髓瘤 (OS) 的新型治疗点.
- 研究调节YAP1调节的谷氨胺代谢通路的潜力,以增强OS对DFMO的反应.
主要方法:
- 利用单细胞和批量转录组数据来分析OS中的聚胺代谢.
- 进行了高通量药物查,以确定与DFMO结合治疗的YAP1抑制剂 (例如,CIL56).
- 在体内 (PDX,CDX模型) 和体外 (分子分析,细胞增殖试验,ROS和谷氨酸代谢研究) 验证的治疗疗效.
主要成果:
- 在晚期和复发性OS细胞中发现了高调节的聚胺代谢.
- DFMO治疗启动了YAP1介导的谷氨酸代谢,通过减少ROS产生抗药性途径.
- 将DFMO与YAP1抑制剂CIL56或谷氨酸酶抑制剂CB-839结合起来,在体外和体内显著增强了治疗疗效.
结论:
- 通过YAP1介导的谷氨胺代谢作为一个关键的绕道机制,在骨髓瘤中对DFMO起作用.
- 准这种途径为转移性和复发性OS提供了一个有希望的"一两拳"治疗策略.
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