ESR13: “Systematic analysis and screening of inhibitors for DNA Repair pathways”

LXRepair: Systematic analysis and screening of inhibitors for DNA Repair pathways.

i. Objective of research: To exploit LXRepair’s functional DNA Repair assays to assess the quantitative functional impact of inhibitors for (i) specific DNA Repair factors, (ii) DDR and (iii) signal transduction pathways for the development of radiosensitization strategies.

ii. Current state of the art: DNA repair pathways and their upstream regulators can enable tumour cells to survive DNA damage created by radiotherapy. Novel compounds that influence DNA repair and DDR processes, are being developed with the idea to sensitize cancer cells to radiotherapy. Moreover, growth factor receptor activation by mutation or overexpression, or mutations in oncogenes or tumour suppressor genes can lead to signalling through the PI3K–AKT, MAPK–ERK, nuclear factor-κB and transforming growth factor-β pathways. Such signalling can affect radiosensitivity by increasing DNA repair. We know that redundant and overlapping functions exists among repair proteins and that DNA repair inhibitors can exert pleiotropic effects. Therefore, there is a pressing need to identify biomarkers to predict the response to the inhibitors. In addition, the establishment of the link between transduction survival pathways and DNA repair is an emerging research field and is not completely understood.

iii. Research methodology and approach: LXRepair has recently developed two innovative fluorescent functional assays that quantitatively measure several enzymatic activities from excision and excision/synthesis repair mechanisms (BER, NER and ICLR). These assays have been successfully used to explore the mechanisms of action of anticancer drugs, better understand the cellular DDR and gain insights into the relationship between drug resistance and activation of specific DNA repair enzymes/pathways. Using the same concept, we generated a functional biochip-based multiplexed assay aiming at quantifying HR and NHEJ. We propose to use a panel of human cell models with DDR inactivated genes to assess the effects of DNA Repair, DDR and relevant signal transduction inhibitors at basal level and in response to genotoxic stress; the latter will allow us to precisely characterize the impact of distinct drugs across DNA repair pathways to obtain specific DNA repair signatures.

iv. Originality and innovative aspects of the ESR project: The results will enable the design of more efficient therapeutic strategies, combining radiotherapy and a battery of specific pathway inhibitors.

v. Integration of the ESR project to the overall research programme: Our ESR13 will work with Genevia, the Garinis and the Schumacher groups to test the relevance of DNA repair inhibitors in cell homeostasis.