Work

The Impact of Poly(ADP-ribose) Polymerase 1 on the Sensitivity of Breast Cancer Type 1/2 Susceptibility Wild-Type Ovarian Cancer Cells to Niraparib

Year: 2026

Type: article

Abstract: Background: The Poly(ADP-ribose) polymerase (PARP) inhibitor niraparib improves survival in ovarian cancer, but its long-term efficacy was limited by acquired resistance. This study aimed to identify the key mechanism underlying acquired niraparib resistance in breast cancer type 1/2 susceptibility (BRCA1/2) wild-type ovarian cancer.Methods: A stable niraparib-resistant cell line was generated by continuous drug exposure for six months (SKOV3_Nira_6M). Transcriptomic profiling (RNA-seq) and Western blot analysis were used to identify key changes in gene and protein expression. Functional roles were assessed by knocking down PARP1 in parental cells and re-expressing it in resistant cells. Drug sensitivity was measured by cell counting kit-8 assay. Cell viability, proliferation, and apoptosis were evaluated using crystal violet staining, 5-ethynyl-2′-deoxyuridine (EdU) assay, and flow cytometry, respectively. In vivo validation was performed using subcutaneous xenograft models in nude mice established with doxycycline-inducible PARP1-knockdown (SKOV3) or PARP1-overexpressing (SKOV3_Nira_6M) stable cell lines.Results: Transcriptomic and protein-level analyses consistently demonstrated a specific and significant downregulation of PARP1 in resistant cells. Knocking down PARP1 in parental SKOV3 cells induced resistance to niraparib, manifested as significantly enhanced cell viability and proliferation, reduced apoptosis, and diminished tumor growth inhibition by niraparib in nude mouse models. Conversely, overexpressing PARP1 in the resistant SKOV3_Nira_6M cells partially restored sensitivity to niraparib, enhancing its cytotoxicity in vitro by inhibiting cell viability and proliferation and promoting apoptosis, while augmenting its inhibitory effect on tumor growth in vivo.Conclusion: Our findings establish that downregulation of the drug target PARP1 is a key driver of acquired niraparib resistance in BRCA1/2 wild-type ovarian cancer, providing new mechanistic insight and identifying a potential target for overcoming clinical resistance.

Source: Discovery Medicine