Lecture Dr. Carine Michiels | Synthetic lethality and senolytic drugs in combination with radiotherapy

Synthetic lethality and senolytic drugs in combination with radiotherapy

Although improvements in radiation therapy were made over the years, radioresistance is still a major challenge. Cancer cells are often deficient for DNA repair response, a feature that is currently exploited as a new anti-cancer strategy. In this context, combination of inhibitors targeting complementary pathways is of interest to sensitize cells to radiation. In our work, combination of PARP and RAD51 inhibitors enhanced persistent DNA damage, delayed apoptosis, prolonged cell cycle arrest and senescence upon irradiation. Furthermore, they radiosensitized cancer cells to proton and X-ray irradiations in different cancer cell lines, an effect which correlated with cell proliferation rate.

Since we showed that treatment with irradiation with either photons or protons combined or not to PARP inhibitors induced senescence, the senescent cells were targeted by Navitoclax (ABT-263), a senolytic drug. An increase in the percentage of cell death was clearly obtained. Then, we determined how PARP inhibitors led to senescent cancer cells. We tested several PARP inhibitors: Veliparib, Rucaparib, Olaparib, Niraparib and Talazoparib. The results of our work demonstrated that Talazoparib induced the strongest phenotype of senescence in several cancer cell lines. These senescent cells could also be specifically targeted by senolytic to increase cell death. 

These results demonstrated that radiation-induced synthetic lethality, used alone or with senolytic drugs might widen the therapeutic window, hence extending the use of PARP inhibitors to patients without BRCAness.