Functional DNA Repair Signature of Cancer Cell Lines Exposed to a Set of Cytotoxic Anticancer Drugs Using a Multiplexed Enzymatic Repair Assay on Biochip

The development of resistances to conventional anticancer drugs compromises the efficacy of cancer treatments. In the case of DNA-targeting chemotherapeutic agents, cancer cells may display tolerance to the drug-induced DNA lesions and/or enhanced DNA repair. However, the role of DNA damage response (DDR) and DNA repair in this chemoresistance has yet to be defined. To provide insights in this challenging area, we analyzed the DNA repair signature of 7 cancer cell lines treated by 5 cytotoxic drugs using a recently developed multiplexed functional DNA repair assay. This comprehensive approach considered the complexity and redundancy of the different DNA repair pathways. Data was analyzed using clustering methods and statistical tests. This DNA repair profiling method defined relevant groups based on similarities between different drugs, thus providing information relating to their dominant mechanism of action at the DNA level. Similarly, similarities between different cell lines presumably identified identical functional DDR despite a high level of genetic heterogeneity between cell lines. Our strategy has shed new light on the contribution of specific repair sub-pathways to drug-induced cytotoxicity. Although further molecular characterisations are needed to fully unravel the mechanisms underlying our findings, our approach proved to be very promising to interrogate the complexity of the DNA repair response. Indeed, it could be used to predict the efficacy of a given drug and the chemosensitivity of individual patients, and thus to choose the right treatment for individualised cancer care.

常规抗癌药物耐药性的产生会削弱癌症治疗的疗效。针对DNA靶向化疗药物而言，癌细胞可对药物诱导的DNA损伤产生耐受，或增强自身DNA修复能力。然而，DNA损伤应答（DNA damage response, DDR）与DNA修复在该化疗耐药性中所发挥的作用仍有待明确。为给这一极具挑战性的研究领域提供新见解，我们借助新近开发的多重功能性DNA修复检测技术，对经5种细胞毒性药物处理的7株癌细胞系的DNA修复特征展开了分析。该综合性研究方法充分考量了不同DNA修复通路的复杂性与冗余性。研究采用聚类分析与统计学检验方法对数据进行处理。该DNA修复谱分析方法可基于不同药物间的相似性划分相关组别，进而获取其在DNA层面的主要作用机制相关信息。同理，尽管不同细胞系间存在高度的遗传异质性，但其相似性仍可提示其具备相同的功能性DDR。本研究策略为阐明特定修复亚通路在药物诱导细胞毒性中的贡献提供了全新视角。尽管尚需开展更多分子表征工作以完全解析本研究结果背后的机制，但本方法已展现出极具前景的应用潜力，可用于解析DNA修复应答的复杂机制。事实上，该方法可用于预测特定药物的疗效以及患者个体的化疗敏感性，从而为个体化癌症诊疗选择合适的治疗方案。