文章：

DNA修复失调从癌症驱动因子到治疗靶点

DNA repair dysregulation from cancer driver to therapeutic target

原文发布日期：2012-11-23

DOI: 10.1038/nrc3399

类型: Review Article

开放获取: 否

要点：

1. The DNA damage response (DDR) coordinates the repair of DNA and the activation of cell cycle checkpoints to arrest the cell to allow time for repair.
2. DNA is subject to a high level of endogenous damage and the DDR is essential for the maintenance of genomic stability and survival.
3. Dysregulation of the DDR can lead to genomic instability that promotes cancer development but that is exploitable with both conventional cytotoxic therapy and DDR inhibitors. Downregulated DDR pathways render the tumour sensitive to specific cytotoxics and some DDR inhibitors. Upregulated DDR pathways confer therapeutic resistance.
4. Inhibitors of the DDR have been developed to overcome resistance and to augment the activity of conventional therapy.
5. Loss of a DDR pathway can lead to dependence on a compensatory pathway, and targeting this second pathway may render endogenous DNA damage cytotoxic by a process termed synthetic lethality, which will be tumour-specific because the normal tissues in the animal (or person) will have functional DNA repair.
6. Despite promising preclinical data combining DDR inhibitors with conventional cytotoxic agents, these combinations have been less successful in the clinic and are often associated with toxicity. Exploitation of DDR defects by synthetic lethality is a more promising approach. Clinical data on the use of poly(ADP-ribose) polymerase (PARP) inhibitors in homologous recombination repair (HRR)-defective tumours are encouraging.
7. Robust and validated biomarkers to identify DDR defects that are exploitable by both conventional cytotoxic therapy and agents targeting the DDR are needed to effectively stratify patients.

要点翻译：

1. DNA损伤应答（DDR）通过协调DNA修复与细胞周期检查点激活，使细胞停滞以争取修复时间。
2. DNA易受高水平内源性损伤，而DDR对维持基因组稳定性及细胞存活至关重要。
3. DDR失调会导致基因组不稳定性，从而促进癌症发展，但这种特性可被传统细胞毒性疗法和DDR抑制剂共同利用。下调的DDR通路使肿瘤对特定细胞毒药物敏感，而上调的DDR通路则会产生治疗抵抗。
4. 为克服耐药性并增强传统疗法疗效，研究人员开发了DDR抑制剂。
5. 当某条DDR通路缺失时，细胞会依赖替代通路进行补偿，靶向这种次级通路可通过“合成致死”效应使内源性DNA损伤产生细胞毒性。该机制具有肿瘤特异性，因为机体正常组织仍保有功能性DNA修复能力。
6. 尽管DDR抑制剂联合传统细胞毒药物的临床前数据令人鼓舞，但这些联合方案在临床实践中成效有限且常伴随毒性。利用合成致死策略靶向DDR缺陷则更具前景，聚腺苷二磷酸核糖聚合酶（PARP）抑制剂用于同源重组修复（HRR）缺陷型肿瘤的临床数据尤其令人振奋。
7. 当前亟需建立经过验证的可靠生物标志物体系，用以识别可被传统细胞毒性疗法和靶向DDR药物共同利用的DDR缺陷，从而实现患者的精准分层治疗。

英文摘要：

Dysregulation of DNA damage repair and signalling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. Dysfunction of one DNA repair pathway may be compensated for by the function of another compensatory DDR pathway, which may be increased and contribute to resistance to DNA-damaging chemotherapy and radiotherapy. Therefore, DDR pathways make an ideal target for therapeutic intervention; first, to prevent or reverse therapy resistance; and second, using a synthetic lethal approach to specifically kill cancer cells that are dependent on a compensatory DNA repair pathway for survival in the context of cancer-associated oxidative and replicative stress. These hypotheses are currently being tested in the laboratory and are being translated into clinical studies.

摘要翻译： 

DNA损伤修复及细胞周期检验点信号传导的失调，即DNA损伤应答（DDR），与癌症易感性相关，并影响对DNA损伤抗癌治疗的反应。某一DNA修复途径的功能障碍可能通过另一代偿性DDR途径的功能得到补偿，该代偿途径可能增强，并导致对DNA损伤化疗和放疗的耐药。因此，DDR通路成为理想的治疗干预靶点：首先，用于预防或逆转治疗耐药；其次，采用合成致死策略，特异性杀伤依赖代偿性DNA修复通路生存的癌细胞，这些癌细胞处于肿瘤相关氧化和复制应激的环境中。这些假设目前正在实验室验证，并正转化为临床研究。

原文链接：

DNA repair dysregulation from cancer driver to therapeutic target