通过向ATR通路,在具有DNA损伤反应缺陷的慢性淋巴细胞白血病中产生合成致死性
Marwan Kwok1, Nicholas Davies1, Angelo Agathanggelou1
1School of Cancer Sciences, University of Birmingham, Birmingham, UK.
Lancet (London, England)
|August 28, 2015
概括
一种新型ATR抑制剂AZD6738有效向具有DNA损伤反应 (DDR) 缺陷的慢性淋巴细胞白血病 (CLL) 细胞,特别是TP53或ATM无活化. 这种方法提供了一种克服治疗耐药性和预防这些患者疾病复发的新策略.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 包括TP53和ATM异常在内的DNA损伤反应 (DDR) 缺陷导致慢性淋巴细胞白血病 (CLL) 的基因组不稳定性和化学抵抗性.
- 目前的治疗方法在患有DDR缺陷的CLL患者中缺乏长期疾病控制的有效性.
- 作为针对这些特定的CLL细胞的合成致死性策略,研究了ATR通路的抑制.
研究的目的:
- 研究一种新型ATR抑制剂AZD6738作为针对TP53或ATM缺陷的CLL细胞的向治疗的疗效.
- 在DDR缺陷的CLL细胞中阐明ATR抑制诱导的合成致死性机制.
主要方法:
- 通过西方涂抹和免疫光检测评估了AZD6738对DDR蛋白的影响.
- 使用光测定和酸排除评估了细胞毒性.
- 在AZD6738治疗后,将原发性CLL细胞与TP53或ATM无活化移植到小鼠体内,并分析瘤负荷/亚克隆组合.
主要成果:
- 在p53或ATM缺乏的CLL细胞中,AZD6738强烈抑制ATR信号传递,诱导DNA损伤和线粒性灾难.
- 这种药物对DDR缺陷的CLL细胞具有选择性细胞毒性,并与化疗产生协同作用.
- 在AZD6738治疗后,体内研究证实了瘤负荷的降低和CLL亚克隆的选择性降低以及ATM或TP53的改变.
结论:
- 在向p53- null或ATM- null的CLL细胞方面,AZD6738的机理洞察力和体外/体内疗效得到了证明.
- 这种新的治疗方法有可能防止克隆进化,这是CLL治疗耐药性和复发的关键驱动因素.
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