AUTHOR=Zouggari Nawel , Trugenberger Camilla , Du Bois Valentine , Wang Wenwen , Rossetti Giacomo G. , Halazonetis Thanos D. , Labidi-Galy Intidhar 

TITLE=CldU sensitizes BRCA2 reverse-mutated cells to PARP inhibitors

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1626301

DOI=10.3389/fonc.2025.1626301

ISSN=2234-943X

ABSTRACT=PARP inhibitors are widely used class of drugs for the treatment of homologous recombination deficient cancers, including BRCA mutated ones. These drugs led to substantial improvement in survival, particularly for patients with BRCA mutated tumors. However, many patients eventually develop resistance to PARP inhibitors, mainly due to BRCA reversion mutations. Overcoming resistance to PARP inhibitors is an unmet medical need. Recently, it has been shown that BRCA-deficient cells are hypersensitive to the thymidine analogue 5-chloro-2’-deoxyuridine (CldU), either alone or in combination with PARP inhibitors. In this study, we show, across multiple BRCA2 mutated cell lines, that CldU sensitizes PARP inhibitor-resistant cells to PARP inhibitors. This synergy was also present in cell lines with BRCA2 reversion mutations and was associated with high levels of DNA damage and arrest in S phase. This effect, which is specific to thymidine analogue CldU, may open new avenues for the treatment of BRCA mutated cancers resistant to PARP inhibitors.