Harnessing DNA Replication Stress for Novel Cancer Therapy.
Harnessing DNA Replication Stress for Novel Cancer Therapy.
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DOI：
10.3390/genes11090990
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发表时间：
2020-08-25
期刊：
影响因子：
3.5
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhu H;Swami U;Preet R;Zhang J
DNA复制是遗传信息准确复制和传递的基本过程。它的保真度处于来自内源性和外源性因素的持续压力下，这些因素可引起导致DNA损伤和复制缺陷的扰动。这可能会损害基因组的稳定性和完整性。基因组不稳定性被认为是癌症的标志之一。在正常细胞中，各种检查点可以激活DNA修复或诱导细胞死亡/衰老。另一方面，由于DNA损伤修复机制缺陷和生长信号不受抑制，癌细胞增强DNA复制应激。虽然复制应激可以导致突变和肿瘤发生，但它可以被矛盾地用于癌症治疗。在此，我们综述了利用复制应激进行癌症治疗的机制和原理。我们讨论了针对DNA复制应激的既有方法和新方法，包括化疗、放疗和针对ATR、Chk 1、PARP、WEE 1、MELK、NAE、TLK等通路的小分子抑制剂。最后，我们回顾了联合治疗、生物标志物，并提出了潜在的靶向DNA复制应激治疗癌症的新方法。
DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.
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