Synergistic effect of XYL-1 and Olaparib in BRCA-proficient TNBC cells is associated with RAD51 and BRCA1 downregulation

Poly-ADP-ribose polymerase1/2 (PARP1/2) inhibitors are approved for HER2-negative breast cancer harboring germline BRCA1/2 mutations, including TNBC. However, the majority of patients with BRCA-proficient derive limited benefit from these agents. In this study, we demonstrate that the efficacy of the PARP1/2 inhibitor Olaparib in BRCA-proficient TNBC cell lines can be markedly enhanced by co-treatment with the PARP7 inhibitor XYL-1. Our results demonstrated that the combination of Olaparib and XYL-1 significantly inhibited the proliferation of BRCA-proficient MDA-MB-231 and MDA-MB-468 cells compared with either monotherapy, with the strongest synergistic effect observed at a 1:1 molar ratio in MDA-MB-231 cells. Furthermore, the combination of Olaparib and XYL-1 significantly increased cellular ROS levels, induced DNA double-strand breaks (DSBs), and ultimately promoted apoptosis. In vivo , the combined treatment significantly suppressed MDA-MB-231 tumor growth compared with either monotherapy, while exhibiting a favorable safety profile. Mechanistically, co-treatment with XYL-1 and Olaparib significantly downregulated RAD51 and BRCA1 expression, which may be associated with impaired homologous recombination (HR)-mediated DNA repair. Collectively, these findings suggest that dual targeting of PARP7 and PARP1/2 represents a promising combination strategy for the treatment of BRCA-proficient TNBC.