Olaparib reverses prostate cancer resistance to Rapamycin by promoting macrophage polarization towards the M1 phenotype

Prostate cancer (PCa) is the most common non-cutaneous malignancy and the second leading cause of cancer-related death in men. Despite its prevalence, treatment outcomes are often unsatisfactory, necessitating the search for more effective therapeutic approaches. mTOR inhibitor Rapamycin (RAPA) has shown promise in managing PCa, but the emergence of resistance often undermines its long-term effectiveness. Recent studies suggest that poly ADP-ribose polymerase (PARP) inhibitor Olaparib (OLP) may overcome drug resistance in various tumor types. This study aims to assess the efficacy of OLP in treating RAPA-resistant PCa, with a specific focus on elucidating its underlying molecular mechanisms. This study utilized drug exposure and concentration escalation experiments to establish human RAPA-resistant PCa cell line (PC-3R) based on the human PCa cell line (PC-3). PC-3R cell lines were screened through a cloning assay. The efficacy of OLP in RAPA-resistant PCa, as well as its regulatory impact on tumor-associated macrophages (TAMs), was evaluated through a combination of real-time PCR, ELISA, immunohistochemistry, and fluorescence experiments. This study unveiled that the combination of OLP and RAPA effectively suppressed the proliferation, stemness, invasion, angiogenesis, apoptosis resistance, and anti-oxidative stress capacity of RAPA-resistant PCa. Additionally, it demonstrated the capacity of OLP to regulate macrophage polarization within the tumor microenvironment and reverse drug resistance to RAPA in PCa. The findings of this study lay a theoretical foundation for the potential utilization of OLP in the treatment of RAPA-resistant PCa, offering substantial academic significance and promising application prospects.