BCLXL blockade rewires cell fate to overcome PARP inhibitor resistance in ovarian cancer

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) induce regressions and extend progression-free survival (PFS) in ovarian cancer, especially in tumors with BRCA1 or BRCA2 mutations that impair homologous recombination repair. While recent studies have clarified the key roles of BRCA1, BRCA2, and PARP1 in replication fork stability, the downstream mechanisms that mediate PARPi-induced cytotoxicity and resistance remain incompletely understood. Here we delineate cell fate outcomes following PARPi treatment in homologous recombination-deficient high-grade serous ovarian cancer and identify actionable pathways to overcome acquired resistance. Our findings reveal that PARPi-induced DNA damage simultaneously triggers apoptosis, which primarily occurs through the BAX/BAK-dependent intrinsic apoptotic pathway, while also driving cellular senescence, as manifested by the expression of senescence-associated β-galactosidase, CDKN1A upregulation and a senescence-associated secretory phenotype. Notably, the PARPi-induced senescent cells persist as resistance develops and exhibit multinucleation, a hallmark of nuclear atypia, both in vitro and in patient-derived xenografts (PDXs).