LINC00467 mediates PARP inhibitor resistance in high-grade serous ovarian cancer by regulating miR-485-5p/RAD50 axis.

PURPOSE: High-grade serous ovarian cancer (HGSOC) is extremely lethal owing to its high risk of recurrence and resistance to common chemotherapy. PARP inhibitor (PARPi) is currently the most promising target drug among patients with HGSOC, but its resistance mechanism remains unclear. In this study, we aimed to investigate the mechanism of PARPi resistance and explore new therapeutic targets. METHODS: We established olaparib-acquired resistant cell lines denoted SKOV3-OR and performed lncRNA sequencing. Biological behavior study illustrated the effect of LINC00467 on HGSOC cells in vitro and vivo. Bioinformatics and the dual-luciferase reporter system confirmed the downstream target genes. Patient-derived xenograft (PDX) models were established to validate the effect of LINC00467 on response to olaparib. RESULTS: LncRNA sequencing revealed that LINC00467 was upregulated in PARPi resistant HGSOC cell and predicted poor prognosis. Biological behavior study comfirmed LINC00467 promoted cell proliferation, metastasis and PARPi resistance in HGSOC. Furthermore, the dual-luciferase reporter system confirmed its function as a competitive endogenous RNA by directly sponging miR-485-5p, which further regulated its target, RAD50. Additionally, LINC00467 ASO played a synergistic role with olaparib in HGSOC PDX models. CONCLUSION: Our results showed that LINC00467 could confer PARPi resistance in HGSOC by regulating the miR-485-5p/RAD50 axis and provide a novel therapeutic target in PARPi synergistic treatment for HGSOC.