Introduction Compared with HRD-negative ovarian cancer patients, HRD-positive patients are more sensitive to platinum-based chemotherapy and benefit from PARPi is more significant. However, there are still some HRD-positive patients with platinum and PARPi resistance, resulting in a poor prognosis.

Methods In this study, a key differential gene, Oxysterol binding protein like 10 (OSBPL10), was identified by bioinformatics analysis of platinum-resistant and platinum-sensitive HRD-positive ovarian cancer patients after first-line chemotherapy in TCGA database. Western Blot and Immunohistochemistry were performed on tumor tissues from Qilu Hospital of Shandong university to verify the differential expression of OSBPL10. Target genes of OSBPL10 were identified by RNA-seq and validated by RIP. In addition, we established PDX models for high-grade serous ovarian cancer (HGSOC) patients to validate the efficacy of targeting OSBPL10.

Results The expression of OSBPL10 in platinum-resistant HRD-positive ovarian cancer patients were significantly higher than that in platinum-sensitive patients. Inhibiting OSBPL10 enhanced the sensitivity to cisplatin and Niraparib of ovarian cancer cells. Apolipoprotein E (APOE), as a target gene of OSBPL10, was involved in lipid transport and lipoprotein metabolism. Overexpression of OSBPL10 could active the expression of APOE, enhance DNA damage repair function, and up-regulate cholesterol levels in intracellular, extracellular and tumor microenvironment, leading to increased exhaustion of CD8⁺ T cells, and further promoting resistance to cisplatin and Niraparib. Combined with Niraparib, OSBPL10 adenovirus (shRNA- OSBPL10) was more effective in repressing tumor growth of PDX models than Niraparib monotherapy.

Conclusion/Implications OSBPL10-APOE pathway regulated DNA damage repair and cholesterol metabolism, leading to cisplatin and Niraparib resistance of HRD-positive HGSOC.