The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo
The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo
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DOI：
10.1182/blood-2010-01-265769
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发表时间：
2010-11-25
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：
Weston, Victoria J.;Oldreive, Ceri E.;Stankovic, Tatjana
共济失调毛细血管扩张突变（ATM）基因在淋巴恶性肿瘤如慢性淋巴细胞白血病（CLL）、T-幼淋巴细胞白血病（T-PLL）和套细胞淋巴瘤（MCL）中经常失活，并且与响应烷化剂和嘌呤类似物的细胞凋亡缺陷相关。ATM突变细胞表现出受损的DNA双链断裂修复。聚（ADP-核糖）聚合酶（PARP）的抑制，施加DNA双链断裂修复的要求，应选择性敏感ATM缺陷的肿瘤细胞杀死。我们研究了5种ATM突变型淋巴母细胞样细胞系（LCL）、1种ATM突变型MCL细胞系、1种ATM敲减PGA CLL细胞系和9种诱导循环的ATM缺陷型原代CLL对聚（ADP-核糖）聚合酶抑制剂奥拉帕尼（AZD 2281）的体外敏感性，并观察到与ATM野生型对应物相比的差异杀伤。ATM和ATM敲低的药理学抑制证实了该效应是ATM依赖性的，并且通过独立于细胞凋亡的有丝分裂灾难介导。ATM突变MCL细胞系的非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠异种移植模型显示，奥拉帕尼体内治疗后，肿瘤负荷显著降低，动物存活率增加。向DNA损伤剂添加奥拉帕尼敏化的ATM无效肿瘤细胞。我们认为奥拉帕尼是治疗难治性ATM突变型淋巴瘤的合适药物。（血。2010; 116（22）：4578-4587）
The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. Anonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors. (Blood. 2010; 116(22): 4578-4587)