Targeting DNA damage response in cancer therapy.
Targeting DNA damage response in cancer therapy.
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DOI：
10.1111/cas.12366
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发表时间：
2014-04
期刊：
影响因子：
5.7
通讯作者：
Miyagawa K
中科院分区：
文献类型：
--
作者：
Hosoya N;Miyagawa K
癌症化疗和放疗主要通过诱导DNA损伤来杀死癌细胞。DNA损伤通常由固有的DNA损伤反应机制识别和修复。如果受损的病变被成功修复，细胞将存活。为了通过诱导DNA损伤的疗法特异性且有效地杀死癌细胞，重要的是利用存在于癌细胞中而不存在于正常细胞中的DNA损伤反应机制中的特异性异常。癌细胞的这些特性可以提供生物标志物或致敏靶点。例如，识别或修复特定类型的DNA损伤的特定途径的缺陷或上调可以作为对诱导此类DNA损伤的疗法的有利或不良反应的生物标志物。DNA损伤反应途径的抑制可以增强与DNA损伤剂组合的治疗效果。此外，当它实现合成致死性时，它也可以用作单一疗法，其中互补DNA损伤反应途径的抑制选择性地杀死在特定DNA修复途径中具有缺陷的癌细胞。该策略最引人注目的应用是通过聚（ADP-核糖）聚合酶抑制剂治疗同源重组缺陷的癌症。在这篇综述中，我们通过解释这些治疗策略目前如何在临床前或临床试验中进行评估，描述了靶向DNA损伤反应中癌症特异性畸变的影响。
Cancer chemotherapy and radiotherapy are designed to kill cancer cells mostly by inducing DNA damage. DNA damage is normally recognized and repaired by the intrinsic DNA damage response machinery. If the damaged lesions are successfully repaired, the cells will survive. In order to specifically and effectively kill cancer cells by therapies that induce DNA damage, it is important to take advantage of specific abnormalities in the DNA damage response machinery that are present in cancer cells but not in normal cells. Such properties of cancer cells can provide biomarkers or targets for sensitization. For example, defects or upregulation of the specific pathways that recognize or repair specific types of DNA damage can serve as biomarkers of favorable or poor response to therapies that induce such types of DNA damage. Inhibition of a DNA damage response pathway may enhance the therapeutic effects in combination with the DNA-damaging agents. Moreover, it may also be useful as a monotherapy when it achieves synthetic lethality, in which inhibition of a complementary DNA damage response pathway selectively kills cancer cells that have a defect in a particular DNA repair pathway. The most striking application of this strategy is the treatment of cancers deficient in homologous recombination by poly(ADP-ribose) polymerase inhibitors. In this review, we describe the impact of targeting the cancer-specific aberrations in the DNA damage response by explaining how these treatment strategies are currently being evaluated in preclinical or clinical trials.
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