ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells
ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells
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DOI：
10.1182/blood-2015-05-644872
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发表时间：
2016-02-04
期刊：
影响因子：
20.3
通讯作者：
Stankovic, Tatjana
中科院分区：
文献类型：
--
作者：
Kwok, Marwan;Davies, Nicholas;Stankovic, Tatjana
TP53和共济失调毛细血管扩张突变（ATM）缺陷与慢性淋巴细胞白血病（CLL）的基因组不稳定性、克隆进化和化疗耐药性相关。目前，缺乏能够在复发性/难治性TP 53缺陷型或ATM缺陷型CLL中提供持久缓解的疗法。共济失调毛细血管扩张症和Rad3相关（ATR）介导对复制应激的反应，缺乏这种应激会导致停滞的复制叉崩溃成染色单体片段，需要通过ATM/p53途径解决。在这里，使用AZD 6738，一种新的ATR激酶抑制剂，我们研究了ATR抑制作为一种合成致死策略，靶向具有TP53或ATM缺陷的CLL细胞。无论TP53或ATM的状态，诱导CLL细胞增殖上调ATR蛋白，然后成为激活复制应激反应。在TP53或ATM缺陷型CLL细胞中，AZD 6738对ATR信号传导的抑制导致未修复DNA损伤的积累，由于细胞周期检查点缺陷，这些损伤被带入有丝分裂，导致细胞因有丝分裂灾难而死亡。因此，AZD 6738对TP53和ATM缺陷型CLL细胞系和原代细胞具有选择性细胞毒性。这在体内使用TP53或ATM缺陷型CLL的原代异种移植模型得到证实，其中AZD 6738治疗导致肿瘤负荷降低和具有此类缺陷的CLL细胞比例降低。此外，AZD 6738使TP53或ATM缺陷的原代CLL细胞对化疗和伊曲替尼敏感。我们的研究结果表明，ATR是一个有前途的治疗目标TP53或ATM缺陷的CLL，值得临床研究。
TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation.