Implication des inhibiteurs de PARP dans le cancer de l’ovaire
Epithelial ovarian cancer (EOC) is the most lethal gynaecological cancer in North America. Poly (ADP-Ribose) Polymerase (PARP) inhibitors have been used to improve treatment; two of which including Olaparib are approved by the FDA. Olaparib demonstrates good efficacy (30% response) as a single agent for patients with ovarian cancer and even more so for those with a mutation in the BRCA1/2 (45%) genes. This result was explained as a consequence of synthetic lethality between the mutants BRCA1/2; which are the principal actors of the DNA repair system by homologous recombination (HR), and the inhibition of PARP, which is the main actor of DNA repair by base excision repair (BER). In patients with no BRCA1/2 mutation (25%), the observed response is also explained by an effect of synthetic lethality, but this time due to either a decline in BRCA1/2 gene expression or the inhibition of other proteins specific to HR (BRCAness effect). In contrast, 55% of BRCA1/2 mutated patients did not respond to treatment. The overall response is only 30%, while 50% of high-grade serous (HGS) EOC patients have an HR deficiency. To try to explain this contradiction, this thesis seeks to define and improve the response to Olaparib in the HGS EOCs. First, a model was developed to study the different responses to PARP inhibitors. To the 12 pre-existing EOC HGS cell lines in the laboratory, 6 new lines presenting with characteristics specific to PARP inhibitors response were characterized and added [TOV2978G, TOV3041G, TOV3291G, OV866 (2), OV4453 (recurrent BRCA2 nonsense mutation of germinal origin) and OV4485 (splice-site mutation BRCA1)]. From this cell model, a new predictive pattern of susceptibility to Olaparib was determined. The idea presented is that the responding patients have an HR deficiency (BRCAness) but that it must be combined with a NER or MMR deficiency. Despite efforts to target these patients and to produce new, more effective PARP inhibitors, the overall response is still around 30%; cases of acquired resistance are increasing and drastic maintenance treatment is still the only way to obtain a clinical response. All this has led us as a third objective to focus on the type of cellular fate induced by the PARP inhibitors allowing us to determine a combination therapy for an improved response. We demonstrate that Olaparib leads to a reversible senescent state in the HGS EOC cell lines despite their TP53 mutations. This condition can be targeted by senolytics (mainly a Bcl2 / Bcl-XL inhibitor) to create a synergistic response when combined with PARP inhibitors. The in vivo experiments confirm the efficacy of the therapeutic combination. This work has contributed to the better identification of patients who are able to respond to PARP inhibitors and to determine a new and particularly effective combination therapy.
mutation BRCA Olaparib NER MMR high-grade serous ovarian epithelial cell line BRCA mutation PARP inhibitors Olaparib DNA repair NER MMR senescence cell cycle arrest therapeutic combination