Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma.
Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma.
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DOI：
10.1158/2159-8290.cd-14-0943
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发表时间：
2015-09
期刊：
影响因子：
28.2
通讯作者：
Tonon G
中科院分区：
文献类型：
--
作者：
Cottini F;Hideshima T;Suzuki R;Tai YT;Bianchini G;Richardson PG;Anderson KC;Tonon G
持续的 DNA 损伤是上皮癌的一个共同特征。在这里，我们发现源自多发性骨髓瘤（MM）（一种克隆性浆细胞疾病）的肿瘤细胞表现出 DNA 复制应激，导致 DNA 损伤。我们发现了预后不良的 MM 亚群，具有广泛的染色体不稳定和复制应激，依赖 ATR 来补偿 DNA 复制应激；相反，ATR 沉默或用特定 ATR 抑制剂治疗会引发 MM 细胞凋亡。我们发现，诸如 MYC 之类的致癌基因不仅通过增加复制应激，而且还通过增加氧化应激来诱导 MM 细胞 DNA 损伤，并且 ROS 诱导剂胡椒长明进一步引发 DNA 损伤和细胞凋亡。重要的是，ATR 抑制与 Piperlongumine 结合可引发协同 MM 细胞毒性。这种合成致死方法增强了氧化应激，同时阻断了复制应激反应，提供了一种新颖的联合靶向疗法，可解决这一 MM 亚型中未得到满足的医疗需求。
Ongoing DNA damage is a common feature of epithelial cancers. Here we show that tumor cells derived from multiple myeloma (MM), a disease of clonal plasma cells, demonstrate DNA replicative stress leading to DNA damage. We identified a poor prognosis subset of MM with extensive chromosomal instability and replicative stress which rely on ATR to compensate for DNA replicative stress; conversely, silencing of ATR or treatment with a specific ATR inhibitor triggers MM cell apoptosis. We show that oncogenes such as MYC induce DNA damage in MM cells not only by increased replicative stress, but also via increased oxidative stress, and that ROS-inducer piperlongumine triggers further DNA damage and apoptosis. Importantly, ATR inhibition combined with piperlongumine triggers synergistic MM cytotoxicity. This synthetic lethal approach, enhancing oxidative stress while concomitantly blocking replicative stress response, provides a novel combination targeted therapy to address an unmet medical need in this subset of MM.