在BPDCN管理的治疗策略中使用Venetoclax
Margaux Poussard1, Maxime Fredon1, Imane Belakri1
1Université Marie et Louis Pasteur, EFS Bourgogne Franche-Comté, INSERM, UMR RIGHT Besançon France.
血细胞状树突细胞瘤 (BPDCN) 的威尼托克拉克斯耐药性涉及BCL- xL上调. 与蛋白质酶抑制剂不同的是,将venetoclax与低甲基化剂结合使用可以克服这种抗药性.
科学领域:
- 癌症学
- 血液学
- 分子生物学
背景情况:
- 威尼托克拉克斯是一种有前途的治疗方法,用于治疗血细胞树突细胞瘤 (BPDCN).
- 报道了复发和对venetoclax的耐药性,但BPDCN中的机制仍未得到研究.
- 这项研究解决了需要了解BPDCN中的venetoclax耐药性的问题.
研究的目的:
- 调查BPDCN中获得的venetoclax抗性的机制.
- 在BPDCN中开发和测试克服venetoclax耐药性的策略.
主要方法:
- 开发了一种慢性venetoclax暴露的体外模型,以诱导BPDCN细胞系的抗药性.
- 使用基因组和蛋白质组分析对抗性细胞系进行了鉴定.
- 评估药物组合以克服venetoclax耐药性
主要成果:
- 获得的耐药性与基因组和蛋白质水平的BCL- xL上调有关.
- 使用venetoclax和低甲基剂的联合治疗克服了抗药性和诱导细胞死亡.
- 与蛋白酶抑制剂的联合治疗未能恢复敏感性,这可能是由于NF- kB途径的改变.
结论:
- 在BPDCN中Venetoclax的耐药性是由BCL-2家族蛋白质平衡的改变引起的.
- 耐药性机制可能会对其他疗法产生交叉耐药性.
- 低甲基化剂是克服BPDCN中毒素耐药性的潜在策略.
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