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Radiation-induced synthetic lethality: combination of poly(ADP-ribose) polymerase and RAD51 inhibitors to sensitize cells to proton irradiation

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journal contribution
posted on 26.06.2019 by Anne-Catherine Wéra, Alison Lobbens, Miroslav Stoyanov, Stéphane Lucas, Carine Michiels

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 this work, we used PARP (Olaparib) and RAD51 (B02) inhibitors to radiosensitize cancer cells to proton and X-ray radiation. More particularly, Olaparib and B02 were used at concentration leading to limited cytotoxic (alone or in combination) but increasing cell death when the cells were irradiated. We showed that, although at limited concentration, Olaparib and B02 were able to radiosensitize different cancer cell lines, i.e. lung and pancreatic cancer cells. Antagonistic, additive or synergistic effects were observed and correlated to cell proliferation rate. The inhibitors enhanced persistent DNA damage, delayed apoptosis, prolonged cell cycle arrest and senescence upon irradiation. These results demonstrated that radiation-induced synthetic lethality might widen the therapeutic window, hence extending the use of PARP inhibitors to patients without BRCAness.

Funding

A.-C. Wéra was a beneficiary of a “Move-In Louvain” incoming post-doctoral fellowship, co-funded by the Marie Curie Action of the European Commission and is now supported by the Belgian Found for Scientific Research (F.R.S-FNRS). The X-ray irradiator was acquired thanks to the support of UNamur, Oncobeth and Solidarité-Espoir (CHU-UCL Namur, Sainte-Elisabeth).

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