State-of-the-art strategies for targeting the DNA damage response in cancer.
State-of-the-art strategies for targeting the DNA damage response in cancer.
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DOI：
10.1038/s41571-018-0114-z
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Yap TA
中科院分区：
文献类型：
--
作者：
Pilié PG;Tang C;Mills GB;Yap TA
基因组不稳定是由于DNA损伤反应(DDR)缺陷和/或复制压力增加而引起的癌症的一个关键标志。这些改变通过累积驱动程序异常，包括基因拷贝数变化、重排和突变，促进了癌细胞的克隆进化；然而，这些相同的缺陷也产生了相对特定于癌细胞的脆弱性，可能被利用来增加抗癌治疗的治疗指数，从而改善患者的预后。BRCA突变的癌细胞对聚(ADP-核糖)聚合酶的抑制非常敏感，这一发现开启了针对不同癌症的生物标记物驱动的合成致死治疗策略研究的新纪元。针对DDR的抗肿瘤药物的治疗范围已迅速扩大，包括其他DNA修复和复制关键介质的抑制剂，如ATM、ATR、CHK1和ChK2、DNA-PK和WEE1。优化这些治疗方法的努力正在一系列癌症中进行，包括开发对反应性的预测性生物标记物分析(超出BRCA突变)，评估内在和获得性耐药的潜在机制，以及评估合理、可耐受的与标准护理治疗(如化疗和放射治疗)、新型分子靶向药物和免疫检查点抑制剂的组合。在这篇综述中，我们讨论了针对DDR的抗癌治疗的现状。
Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.
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影响因子：
--
作者：
Borst GR;Kumareswaran R;Yücel H;Telli S;Do T;McKee T;Zafarana G;Jonkers J;Verheij M;O'Connor MJ;Rottenberg S;Bristow RG
通讯作者：
Bristow RG
影响因子：
28.2
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
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Turner, Nicholas C.
影响因子：
5.3
作者：
Bindra, RS;Schaffer, PJ;Glazer, PM
通讯作者：
Glazer, PM
DOI：
10.1158/1078-0432.ccr-12-3791
发表时间：
2013-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Aparicio AM;Harzstark AL;Corn PG;Wen S;Araujo JC;Tu SM;Pagliaro LC;Kim J;Millikan RE;Ryan C;Tannir NM;Zurita AJ;Mathew P;Arap W;Troncoso P;Thall PF;Logothetis CJ
通讯作者：
Logothetis CJ
影响因子：
14.9
作者：
Bhattacharya S;Srinivasan K;Abdisalaam S;Su F;Raj P;Dozmorov I;Mishra R;Wakeland EK;Ghose S;Mukherjee S;Asaithamby A
通讯作者：
Asaithamby A