Abstract
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.
Highlights
Despite active research and the development of target-specific therapies, resistance to standard cytotoxic drugs still represents a challenge in cancer treatment
Concluding remarks Because DNA damage response (DDR) and DNA repair mechanisms constitute a dynamic network of finely tuned pathways with coordinated back-up and redundancy, comprehensive functional assays that enable DNA repair activities to be measured are promising
We showed that this hypothesis-generating strategy provided new, novel information on the cell lines and on drugs studied
Summary
Despite active research and the development of target-specific therapies, resistance to standard cytotoxic drugs still represents a challenge in cancer treatment. An important factor that affects the cytotoxic effect of these drugs is the ability of tumour cells to sense a variety of DNA lesions and elicit a coordinated response including activation of transcription, cell cycle arrest, apoptosis and DNA repair processes [1,2]. This global DNA damage response (DDR) may lead to tolerance to the drug-induced DNA lesions or to enhanced repair [3,4], preventing an ideal outcome for patients after chemotherapy. Interstrand cross-links (ICLs) are repaired through multiple mechanisms, either recombination-dependent or recombination-independent, with possible cooperation of proteins from NER and mismatch repair (MMR) pathways [17,18]
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