向MCL-1和MAPK克服了FLT3-ITD阳性AML细胞中活性PTPN11 (SHP-2) 突变的venetoclax耐药性
Maximilian Fleischmann1, Ole Hansen1, Diana Voigtländer1
1Department of Hematology and Medical Oncology, Clinic for Internal Medicine II, Comprehensive Cancer Center Central Germany-Campus Jena, University Hospital Jena, Jena, Germany.
British journal of haematology
|January 29, 2026
概括
在急性髓性白血病 (AML) 中,维尼托克拉克斯的耐药性与PTPN11突变有关. 将Venetoclax与MCL-1抑制剂和MEK抑制剂结合使用,有望克服AML的耐药性.
科学领域:
- 血液学 血液学 血液学
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 基于Venetoclax (VEN) 的疗法对于急性髓性白血病 (AML) 治疗至关重要.
- 对VEN的耐药性,通常与PTPN11和FLT3-ITD突变相关,限制了治疗疗效.
- 这些突变激活MAPK信号,增加抗亡蛋白MCL-1和BCL.
研究的目的:
- 调查AML中PTPN11突变介导的VEN耐药性的机制.
- 为了评估VEN与MCL-1和MEK抑制剂结合的疗效.
- 为具有特定突变的高风险AML患者确定潜在的治疗策略.
主要方法:
- Ba/F3细胞被设计为表达野生类型或突变PTPN11 (PTPN11-E76K) 和FLT3-ITD变体.
- 细胞和初级AML样本用VEN,MCL-1抑制剂S63845和MEK抑制剂美丁尼 (TRA) 进行治疗.
- 分析了药物敏感性和蛋白质表达特征.
主要成果:
- 表达PTPN11-E76K的细胞表现出显著的VEN耐药性,ERK激活升高,MCL-1和BCL.
- 结合VEN和MCL-1抑制显著增加了细胞灭绝.
- 与TRA的同时治疗显示出协同效应,特别是在PTPN11突变细胞中.
结论:
- PTPN11和FLT3突变是AML中VEN耐药性的关键驱动因素.
- 由MAPK驱动的MCL-1和BCL(x) L表达介于VEN电阻.
- 双抑制BCL-2和MCL-1,可能被MEK抑制增强,为PTPN11突变的AML提供了一个有希望的治疗方法.
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