摘要
合成致死是指两个非致死性基因同时失活从而导致细胞死亡的现象.近来,合成致死原理已经成功用于癌症精准治疗.癌症在其发生、发展和恶化过程中,积累了大量不能靶向的驱动突变,我们可以用药物精准抑制这些突变的合成致死搭档,从而特异性杀死癌细胞,不危害健康细胞.本文详细介绍了癌症的驱动突变,探讨了合成致死原理及其在癌症精准治疗中的应用;进一步探讨了基于DNA修复机制的BRCA1/2缺陷,激活RAS突变,MYC突变,肿瘤抑制基因TP53以及功能性缺失PTEN的合成致死性研究进展;最后展望了这种策略在无法靶向的驱动突变应用前景,为实现更有效、毒性更低的精准治疗提供方向,是抗癌药物研究的新热点.
Cancer is a leading cause of death in both developed and developing countries.Most cancers occur as a result of somatically acquired alternations in the genomes of normal cells.The somatic alterations presented in a cancer genome can reach about ten thousands.However,a few such alterations that are able to drive initiation and progression of cancer are defined as＂driver＂mutations,while all other mutations are assumed to be randomly acquired and termed as＂passenger＂mutations.Driver mutations confer growth advantage on the cells carrying them and have been positively selected during the evolution of the cancer.Accumulating driver mutations in a cell genome likely result in multi-step mutations of encoded proteins or non-coding transcripts,which change their biological functions of the proteins and transcripts.Driver mutations potentially have been classified into two categories：＂oncogenes＂that are likely resulted from gain-of-function mutations and＂tumor suppressor genes＂that may be due to loss-of-function mutations.Together these two types of mutations drive cancer initiation and development.Targeting driver gene mutations have been successfully applied to the treatment of various cancers in humans.In this review,we introduce the concept of driver and passenger mutations,and theory of synthetic lethality（SL）.Furthermore,we address the application of SL by targeting synthetic lethal partner of these＂driver＂genes and the clinical trial that can be designed based on the theory of SL.Synthetic lethal interactions arise when the perturbation of more than one genes simultaneously results in the loss of viability,whereas a deficiency in only one of these genes does not.SL might be extended to synthetic sickness,which is referred to the sickness but not lethality in cells resulting from mutations of those genes,and synthetic dosage lethality by targeting its partner to kill cells with overexpression of one gene.This theory has been applied to genetic studies to determine functional interactions among different genes for decades and has been exploited for the development of new genotype-selective anticancer agents in engineered human tumor cells.In precision oncology,the theory of SL provides greater promise in specifically targeting cancer cells with genetic mutations but not in normal cells.For example,targeting both of the breast-cancer susceptibility genes 1 and 2（BRCA1 and BRCA2）deficiencies dramatically sensitized cells to poly（ADP-ribose）polymerase（PARP）inhibitors due to associated defective homologous recombination,which leads to dysfunction of DNA repair in cancer cells.Moreover,oncogenic drivers such as RAS,P53 are not＂druggable＂,but recently these oncogenic drivers have been studied in successfully screening for their synthetic lethal partners or agents.If a synthetic lethal agent can be combined with conventionally chemotherapy,this will probably benefit cancer patients.Therefore,the application of the SL in cancer researches and clinical trials might represent one of the most important technological breakthrough in the treatment of cancer in the era of precision oncology.
作者
乔红霞
黄国翔
黄映辉
高山
Hongxia Qiao;Kuohsiang Huang;Yinghui Huang;Shan Gao(College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China;CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences Suzhou 215163, China)
出处
《科学通报》
EI
CAS
CSCD
北大核心
2018年第12期1123-1129,共7页
Chinese Science Bulletin
基金
国家重点研发计划(2016YFC1302100)
国家自然科学基金(81472827和81773023)
中国科学院“百人计划”
中国科学院前沿科学重点研究项目(QYZDB-SSW-SMC038)资助
