Department of Oncology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan.
Hum Genet. 2010 Dec;128(6):567-75. doi: 10.1007/s00439-010-0900-x. Epub 2010 Oct 26.
Synthetic lethal interaction is defined as a combination of two mutations that is lethal when present in the same cell; each individual mutation is non-lethal. Synthetic lethal interactions attract attention in cancer research fields since the discovery of synthetic lethal genes with either oncogenes or tumor suppressor genes (TSGs) provides novel cancer therapeutic targets. Due to the selective lethal effect on cancer cells harboring specific genetic alterations, it is expected that targeting synthetic lethal genes would provide wider therapeutic windows compared with cytotoxic chemotherapeutics. Here, we review the current status of the application of synthetic lethal screening in cancer research fields from biological and methodological viewpoints. Very recent studies seeking to identify synthetic lethal genes with K-RAS and p53, which are known to be the most frequently occurring oncogenes and TSGs, respectively, are introduced. Among the accumulating amount of research on synthetic lethal interactions, the synthetic lethality between BRCA1/2 and PARP1 inhibition has been clinically proven. Thus, both preclinical and clinical data showing a preferential anti-tumor effect on BRCA1/2 deficient tumors by a PARP1 inhibitor are the best examples of the synthetic lethal approach of cancer therapeutics. Finally, methodological progress regarding synthetic lethal screening, including barcode shRNA screening and in vivo synthetic lethal screening, is described. Given the fact that an increasing number of synthetic lethal genes for major cancerous genes have been validated in preclinical studies, this intriguing approach awaits clinical verification of preferential benefits for cancer patients with specific genetic alterations as a clear predictive factor for tumor response.
合成致死相互作用被定义为两种突变同时存在于同一细胞中时导致致死的组合；每个单独的突变是非致死的。在癌症研究领域中，合成致死相互作用引起了人们的关注，因为发现与致癌基因或肿瘤抑制基因（TSG）的合成致死基因提供了新的癌症治疗靶点。由于对携带特定遗传改变的癌细胞具有选择性致死作用，预计靶向合成致死基因将提供比细胞毒性化学疗法更宽的治疗窗口。在这里，我们从生物学和方法学的角度回顾了合成致死筛选在癌症研究领域中的应用现状。介绍了最近寻求鉴定与 KRAS 和 p53 具有合成致死性的基因的研究，KRAS 和 p53 分别是最常见的致癌基因和 TSG。在合成致死相互作用的大量研究中，BRCA1/2 和 PARP1 抑制之间的合成致死性已在临床上得到证实。因此，BRCA1/2 缺陷肿瘤中 PARP1 抑制剂具有优先抗肿瘤作用的临床前和临床数据是癌症治疗中合成致死方法的最佳范例。最后，描述了合成致死筛选的方法学进展，包括条形码 shRNA 筛选和体内合成致死筛选。鉴于越来越多的主要癌症基因的合成致死基因在临床前研究中得到了验证，这种引人入胜的方法正在等待特定遗传改变的癌症患者的临床验证，这些改变是肿瘤反应的明确预测因子，以证明其具有优先获益的潜力。
