文章：

解除管制的DNA损伤信号对癌症化疗反应和耐药性的影响

The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance

原文发布日期：2012-08-24

DOI: 10.1038/nrc3342

类型: Review Article

开放获取: 否

要点：

1. DNA repair defects are targets for chemotherapy drugs.
2. DNA damage response (DDR) genes are also targets for resistance mechanisms that are acquired during chemotherapy treatment.
3. To enhance chemotherapy response, the DDR may be targeted by reactivation of p53, by inhibition of cell cycle checkpoints or by inhibition of DNA repair processes.
4. Therapy resistance of homologous recombination (HR)-deficient tumours may be caused by genetic reversion of the HR defect, by residual HR activity, by rewiring of DNA repair pathways or by tumour heterogeneity.
5. Robust biomarkers are required to maximize the effectiveness of therapy targeting HR deficiency.
6. The best possible treatments might involve combinations of chemotherapy drugs and/or targeted therapeutics to eradicate tumours before resistant tumour cell clones arise.

要点翻译：

1. DNA修复缺陷是化疗药物的作用靶点。
2. DNA损伤反应（DDR）基因也是化疗过程中产生的耐药机制的作用靶点。
3. 为增强化疗反应，可通过重新激活p53、抑制细胞周期检查点或抑制DNA修复过程来靶向DDR。
4. 同源重组（HR）缺陷肿瘤的疗法耐药性可能由HR缺陷的遗传逆转、残留HR活性、DNA修复通路重组或肿瘤异质性引起。
5. 需要可靠的生物标志物来最大化针对HR缺陷的疗法效果。
6. 最佳治疗方案可能涉及联合使用化疗药物和/或靶向治疗，以在耐药肿瘤细胞克隆出现前彻底清除肿瘤。

英文摘要：

Tumours with specific DNA repair defects can be completely dependent on back-up DNA repair pathways for their survival. This dependence can be exploited therapeutically to induce synthetic lethality in tumour cells. For instance, homologous recombination (HR)-deficient tumours can be effectively targeted by DNA double-strand break-inducing agents. However, not all HR-defective tumours respond equally well to this type of therapy. Tumour cells may acquire resistance by invoking biochemical mechanisms that reduce drug action or by acquiring additional alterations in DNA damage response pathways. A thorough understanding of these processes is important for predicting treatment response and for the development of novel treatment strategies that prevent the emergence of therapy-resistant tumours.

摘要翻译： 

具有特定DNA修复缺陷的肿瘤可完全依赖备用DNA修复通路维持存活。这种依赖性可被治疗性利用，通过合成致死效应诱导肿瘤细胞死亡。例如，同源重组（HR）缺陷的肿瘤可被DNA双链断裂诱导剂有效靶向。然而，并非所有HR缺陷肿瘤均对此类疗法同等敏感。肿瘤细胞可能通过激活减少药物作用的生化机制，或在DNA损伤反应通路中获得额外改变而产生耐药性。深入理解这些过程对于预测治疗反应及开发防止治疗抵抗肿瘤出现的新型治疗策略至关重要。

原文链接：

The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance