重定位的转硫驱动 BRAF-V600E 向治疗在黑色素瘤中的耐药性
Klaudia Borbényi-Galambos1, Katalin Erdélyi2, Tamás Ditrói2
1Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hajdú-Bihar County, 4032, Hungary.
Cell metabolism
|March 4, 2025
概括
BRAF V600E 抑制剂对黑色素瘤有效,但出现了耐药性. 通过使用CSE抑制剂以及BRAF抑制剂向囊代谢,可以克服耐药性并改善患者的治疗结果.
科学领域:
- 在瘤学瘤学.
- 癌症新陈代谢 癌症新陈代谢
- 药物耐药性 药物耐药性 药物耐药性
背景情况:
- 布拉夫V600E抑制剂是治疗黑色素瘤的关键药物.
- 获得的耐药性限制了BRAF V600E抑制剂的长期疗效.
- 了解耐药机制对于改善黑色素瘤治疗至关重要.
研究的目的:
- 为了研究使黑色素瘤细胞在BRAF V600E抑制下生存的代谢适应.
- 确定治疗策略,以克服黑色素瘤中耐药性的治疗方法.
主要方法:
- 在各种黑色素瘤模型中分析蛋白质表达,线粒体能量学,代谢学和流动学.
- 对耐药性持续性细胞生存机制的评估.
- 评估与BRAF V600E和cystathionine-γ-lyase (CSE) 抑制剂的联合治疗.
主要成果:
- 黑色素瘤细胞重编程代谢途径 (谷氨酸分解,糖分解,ETC) 并表现出氧化应激反应以求生存.
- 氨酸代谢,特别是增加的CSE活性,对于持续性细胞存活至关重要.
- 结合BRAF V600E和CSE抑制剂,可以减少模型中的复发,并改善小鼠的生存率.
结论:
- 代谢重编程和囊代谢的改变是黑色素瘤中BRAF抑制剂耐药性的关键.
- 针对CSE提供了一个有希望的策略,以提高BRAF V600E抑制剂的疗效.
- 联合抑制可以改善黑色素瘤患者的治疗结果.
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