PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

Abstract Olaparib, a PARP inhibitor, is a targeted therapy used in treating various cancers including castration-resistant prostate cancer (CRPC). Despite its efficacy, resistance to Olaparib remains a significant challenge. Understanding the molecular mechanisms underpinning this resistance is crucial for developing more effective treatment strategies. This study focuses on elucidating the role of mitochondrial alterations and the PINK1 gene in conferring Olaparib resistance in CRPC cells. We investigated the transcriptomic and functional differences in mitochondrial activity between Olaparib-resistant (2B-OlapR, LN-OlapR) and treatment naïve prostate cancer (PCa) cells (C4-2B, LNCaP) in both castration sentitive and resistant settings. Through RNA sequencing and Gene Set Enrichment Analysis (GSEA), we identified significant enrichment of mitochondrial and oxidative phosphorylation-related gene sets in Olaparib Resistant derived cell lines. Resistant lines exhibited enhanced mitochondrial functionality including increased basal and maximal respiration rates, as well as elevated ATP production and spare respiratory capacity compared to parental cells. Subsequent investigations revealed a substantial increase in mitochondrial mass and electron transport chain complex I activity in Olaparib-resistant cells. Furthermore, overexpression of the PINK1 gene was observed in resistant cells, which was correlated with resistance to Olaparib and poor clinical outcomes in prostate cancer patients. Inhibition of PINK1 expression significantly reduced mitochondrial function and mass, impaired cell growth, and decreased resistance to Olaparib. These findings suggest that PINK1 plays a crucial role in modulating mitochondrial dynamics that confer therapeutic resistance, highlighting its potential as a therapeutic target for overcoming Olaparib resistance in PCa.