Radiotherapy is one of the most common forms of anti-cancer treatment. Interestingly, most of these therapies are known to trigger cellular senescence which corresponds to a state of permanent proliferation arrest. In the context of cancer, senescence can have a dual influence. Indeed, senescence has been described to have pro-tumoral and anti-tumoral effects. In the first part of this work, we showed that treatment with irradiation with either photons or protons combined or not to PARP inhibitors induced senescence. Indeed, an increase in the percentage of senescent cells treated with photons or protons was demonstrated. The percentage of senescent cells further increased when cancer cells were treated with photons or protons combined to PARP inhibitors. Moreover, we showed that the senescent cells could be targeted by Navitoclax (ABT-263), a senolytic, in order to increase the percentage of cell death. In the second part of this work, we determined how PARP inhibitors led to senescent cancer cells. We tested several PARP inhibitors: Veliparib, Rucaparib, Olaparib, Niraparib and Talazoparib onto different cancer cells. The results of our work demonstrated that Talazoparib induced the strongest phenotype of senescence in several cancer cell lines. Since all the inhibitors completely abrogated the catalytic activity of PARP, we are currently trying to understand if the differential induction of senescence by inhibitors of PARP is linked to the trapping of PARP1 onto the DNA by the inhibitors. In conclusion, this PhD thesis demonstrated that irradiation with photons or protons significantly increased the percentage of senescent cells, and that combination with PARP inhibitors further increased the percentage of senescent cells. Moreover, the senescent cells could be specifically targeted by senolytic to increase cell death. These preliminary results described a new therapeutic venue for cancer patients treated with conventional radiotherapy, protontherapy or inhibitors of PARP.
|Date of Award||28 Oct 2022|
|Supervisor||Carine MICHIELS (Supervisor), Stephane Lucas (President), Florence Debacq-Chainiaux (Jury), Olivier Féron (Jury), Sophie Lucas (Jury), Anne-Catherine Wera (Jury) & Nicolas Malaquin (Jury)|