Over the past decades, it is recognized that loss of DNA damage repair (DDR) pathways is an early and frequent event in tumorigenesis, occurring in 40-50% of many cancer types. The basis of synthetic lethality in cancer therapy is DDR deficient cancers dependent on backup DNA repair pathways. In cancer, the concept of synthetic lethality has been extended to pairs of genes, in which inactivation of one by deletion or mutation and pharmacological inhibition of the other leads to death of cancer cells whereas normal cells are spared the effect of the drug. The paradigm study is to induce cell death by inhibiting PARP in BRCA1/2 defective cells. Since the successful application of PARP inhibitor, a growing number of developed DDR inhibitors are ongoing in preclinical and clinical testing, including ATM, ATR, CHK1/2 and WEE1 inhibitors. Combination of PARP inhibitors and other DDR inhibitors, or combination of multiple components of the same pathway may have great potential synthetic lethality efficiency. As epigenetics joins Knudson’s two hit theory, silencing of DDR genes by aberrant epigenetic changes provide new opportunities for synthetic lethal therapy in cancer. Understanding the causative epigenetic changes of loss-of-function has led to the development of novel therapeutic agents in cancer. DDR and related genes were found frequently methylated in human cancers, including BRCA1/2, MGMT, WRN, MLH1, CHFR, P16 and APC. Both genetic and epigenetic alterations may serve as synthetic lethal therapeutic markers.

中文翻译：

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基于表观遗传学的人类癌症合成致死策略

在过去的几十年中，人们认识到DNA损伤修复（DDR）途径的丧失是肿瘤发生中的早期和频繁事件，在许多癌症类型中占40-50％。癌症治疗中合成致死性的基础是依赖于备用DNA修复途径的DDR缺陷型癌症。在癌症中，合成致死性的概念已扩展到成对的基因，其中通过缺失或突变使一个基因失活以及对另一种药物的药理抑制会导致癌细胞死亡，而正常细胞则不受药物作用。范式研究是通过抑制BRCA1 / 2缺陷细胞中的PARP诱导细胞死亡。自成功应用PARP抑制剂以来，越来越多的开发中的DDR抑制剂正在临床前和临床测试中进行，包括ATM，ATR，CHK1 / 2和WEE1抑制剂。PARP抑制剂和其他DDR抑制剂的组合，或同一途径的多种成分的组合，可能具有很大的潜在合成杀伤效率。随着表观遗传学加入克努森的两个命中理论，表观遗传学异常变化使DDR基因沉默，为癌症的合成致死疗法提供了新的机会。了解功能丧失的致病性表观遗传学变化已导致开发出新型的癌症治疗药物。在人类癌症中，经常发现DDR和相关基因甲基化，包括BRCA1 / 2，MGMT，WRN，MLH1，CHFR，P16和APC。遗传和表观遗传改变均可作为合成致死性治疗标记。随着表观遗传学加入克努森的两个命中理论，表观遗传学异常变化使DDR基因沉默，为癌症的合成致死疗法提供了新的机会。了解功能丧失的致病性表观遗传学变化已导致开发出新型的癌症治疗药物。在人类癌症中，经常发现DDR及其相关基因甲基化，包括BRCA1 / 2，MGMT，WRN，MLH1，CHFR，P16和APC。遗传和表观遗传改变均可作为合成致死性治疗标记。随着表观遗传学加入克努森的两个命中理论，异常表观遗传学改变对DDR基因的沉默为癌症的合成致死疗法提供了新的机会。了解功能丧失的致病性表观遗传学变化已导致开发出新型的癌症治疗药物。在人类癌症中，经常发现DDR及其相关基因甲基化，包括BRCA1 / 2，MGMT，WRN，MLH1，CHFR，P16和APC。遗传和表观遗传改变均可作为合成致死性治疗标记。在人类癌症中，经常发现DDR和相关基因甲基化，包括BRCA1 / 2，MGMT，WRN，MLH1，CHFR，P16和APC。遗传和表观遗传改变均可作为合成致死性治疗标记。在人类癌症中，经常发现DDR及其相关基因甲基化，包括BRCA1 / 2，MGMT，WRN，MLH1，CHFR，P16和APC。遗传和表观遗传改变均可作为合成致死性治疗标记。