Development of synthetic lethality anticancer therapeutics.
Development of synthetic lethality anticancer therapeutics.
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DOI：
10.1021/jm500415t
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发表时间：
2014-10-09
影响因子：
7.3
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Fang B
合成致死性的概念（从两个或多个基因突变的组合效应中产生致死表型）最近已被用于开发新的基因型选择性抗癌疗法的各种努力。这些努力包括筛选新的抗癌药物，确定新的治疗靶点，表征靶向治疗的耐药机制，以及通过合理设计联合治疗来提高疗效。本文综述了合成致死性抗癌药物的最新进展，包括用于BRCA 1和BRCA 2突变型癌症的聚ADP-核糖聚合酶抑制剂，用于p53突变型癌症的检查点抑制剂，以及靶向RAS基因突变型癌症的小分子药物。由于癌症是由多个基因的突变和多个信号通路的异常引起的，因此特定肿瘤抑制基因或癌基因的合成致死性可能依赖于细胞环境。描述合成致死性的潜在机制和识别治疗反应生物标志物对于合成致死性抗癌治疗的成功至关重要。
The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy.
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