CldU sensitizes BRCA2 reverse-mutated cells to PARP inhibitors

PARP inhibitors are widely used class of drugs for the treatment of homologous recombination deficient cancers, including <i>BRCA</i> mutated ones. These drugs led to substantial improvement in survival, particularly for patients with <i>BRCA</i> mutated tumors. However, many patients eventually develop resistance to PARP inhibitors, mainly due to <i>BRCA</i> reversion mutations. Overcoming resistance to PARP inhibitors is an unmet medical need. Recently, it has been shown that <i>BRCA</i>-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 <i><i>BRCA</i>2</i> mutated cell lines, that CldU sensitizes PARP inhibitor-resistant cells to PARP inhibitors. This synergy was also present in cell lines with <i><i>BRCA</i>2</i> 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 <i>BRCA</i> mutated cancers resistant to PARP inhibitors.