MEK1/2调节正常的BCR和ABL1瘤抑制功能,以决定TKI耐药Ph+白血病中的ATO反应
Laura Mazzera1,2, Manuela Abeltino2, Guerino Lombardi1
1Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna "Bruno Ubertini", Brescia, Italy.
Leukemia
|June 29, 2023
概括
一个新发现的MEK1/2/BCR::ABL1信号循环驱动了白血病中对氨酸激酶抑制剂 (TKI) 的耐药性. 用三氧化 (ATO) 阻断MEK1/2使白血病细胞重新敏感于治疗.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 氨酸激酶抑制剂 (TKI) 耐药性是治疗费城染色体阳性 (Ph+) 慢性髓性白血病 (CML) 的一个主要障碍.
- 了解新型耐药机制对于开发针对TKI耐性白血病的有效治疗策略至关重要.
研究的目的:
- 阐明慢性髓性白血病中TKI耐药性的机械基础.
- 研究三氧化 (ATO) 和MEK1/2抑制剂在克服TKI耐药性的潜力.
主要方法:
- 研究了一种新的MEK1/2/BCR::ABL1信号循环在TKI抗性白血病细胞中.
- 使用了MEK1/2和三氧化 (ATO) 治疗的药理学阻断.
- 在BCR::ABL1诱导白血病的细胞和小鼠模型中评估了联合MEK1/2抑制和ATO的影响.
主要成果:
- 激活的MEK1/2与BCR::ABL1,BCR和ABL1形成复合体,促进导致药物耐药性的酸化事件.
- 抑制MEK1/2会破坏这个复合体,导致脱,恢复瘤抑制功能,使细胞对ATO敏感.
- 与MEK1/2抑制剂Mirdametinib和ATO的联合治疗在TKI耐性白血病的小鼠模型中显著改善了生存率.
结论:
- 一个MEK1/2/BCR::ABL1信号循环被确定为慢性髓性白血病中TKI耐药性的关键驱动因素.
- 针对MEK1/2与ATO结合,显示出显著的抗白血病活性,并克服了TKI耐药性.
- 这种组合疗法对治疗TKI耐药的费城染色体阳性白血病具有治疗性前景.
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