ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors.
ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors.
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DOI：
10.1158/1535-7163.mct-09-0872
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发表时间：
2010-02
影响因子：
5.7
通讯作者：
Lees-Miller SP
中科院分区：
文献类型：
--
作者：
Williamson CT;Muzik H;Turhan AG;Zamò A;O'Connor MJ;Bebb DG;Lees-Miller SP
抑制多聚ADP核糖聚合酶-1(PARP-1)对乳腺癌和卵巢癌易感基因BRCA1或BRCA2突变的细胞是有毒的，这一概念被称为合成致死性。然而，这种方法是否适用于其他DNA修复基因缺陷的人类癌症还有待确定。共济失调-毛细血管扩张突变(ATM)基因在包括套细胞淋巴瘤(MCL)在内的许多人类癌症中发生改变。在这里，我们描述了一组MCL细胞株的ATM状态和功能，并研究了在存在PARP-1小分子抑制剂的情况下，MCL合成致死性的可能性。我们发现，Granta-519和UPN2细胞具有低水平的ATM蛋白，在DNA损伤诱导的ATM依赖信号转导中存在缺陷，对辐射敏感，并存在细胞周期检查点缺陷：所有这些特征都具有缺陷的ATM功能。值得注意的是，Granta-519和UPN2细胞对PARP-1抑制比ATM熟练的MCL细胞更敏感。此外，PARP-1抑制剂olaparib(以前称为AZD2281/KU-0059436)显著减少了肿瘤的生长，并增加了荷有atm缺陷的Granta-519细胞皮下移植的小鼠的总存活率，而对atm熟练的细胞系Z138皮下移植的小鼠的总存活率只有轻微的影响。因此，PARP抑制剂在治疗MCL方面具有治疗潜力，合成致死性的概念扩展到具有ATM改变的人类癌症。
Poly-ADP ribose polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept, termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The Ataxia-Telangiectasia Mutated (ATM) gene is altered in a number of human cancers including Mantle Cell Lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition, than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (previously known as AZD2281/KU-0059436) significantly decreased tumour growth and increased overall survival in mice bearing subcutaneous xenografts of ATM-deficient Granta-519 cells, while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL and the concept of synthetic lethality extends to human cancers with ATM alterations.