Cancer Research UK Gene Function and Regulation Group, The Institute of Cancer Research, London, United Kingdom.
Cancer Res. 2011 Mar 1;71(5):1836-48. doi: 10.1158/0008-5472.CAN-10-2836. Epub 2011 Jan 17.
Synthetic lethal approaches to cancer treatment have the potential to deliver relatively large therapeutic windows and therefore significant patient benefit. To identify potential therapeutic approaches for cancers deficient in DNA mismatch repair (MMR), we have carried out parallel high-throughput RNA interference screens using tumor cell models of MSH2- and MLH1-related MMR deficiency. We show that silencing of the PTEN-induced putative kinase 1 (PINK1), is synthetically lethal with MMR deficiency in cells with MSH2, MLH1, or MSH6 dysfunction. Inhibition of PINK1 in an MMR-deficient background results in an elevation of reactive oxygen species and the accumulation of both nuclear and mitochondrial oxidative DNA lesions, which likely limit cell viability. Therefore, PINK1 represents a potential therapeutic target for the treatment of cancers characterized by MMR deficiency caused by a range of different gene deficiencies.
合成致死方法治疗癌症具有提供相对较大治疗窗口的潜力，因此对患者有显著益处。为了鉴定在 DNA 错配修复（MMR）缺陷的癌症中有潜在治疗方法，我们使用 MSH2 和 MLH1 相关 MMR 缺陷的肿瘤细胞模型进行了平行的高通量 RNA 干扰筛选。我们表明，PTEN 诱导的假定激酶 1（PINK1）的沉默与 MSH2、MLH1 或 MSH6 功能障碍的细胞中的 MMR 缺陷是合成致死的。在 MMR 缺陷背景下抑制 PINK1 会导致活性氧的增加以及核和线粒体氧化 DNA 损伤的积累，这可能限制细胞活力。因此，PINK1 代表了一种潜在的治疗靶点，可用于治疗由一系列不同基因缺陷引起的 MMR 缺陷的癌症。
