Reversion of taxane resistance through PRMT5 inhibition in castration-resistant prostate cancer

The most common cancer in men is prostate cancer (PCa), and the first-line treatment for PCa is the surgical intervention of the tumor and/or chemical castration and radiotherapy. Despite the initial efficacy of this treatment, a stage known as castration-resistant prostate cancer (CRPCa) is eventually reached by a majority of patients within 2 to 3 years. At this stage, chemotherapeutic drugs like taxanes (such as Docetaxel and Cabazitaxel) are considered as treatment options. However, a significant clinical challenge emerges withathe development of drug resistance over time. Epigenetic regulation in cancer has a significant impact on tumor development and progression, as well as chemotherapy resistance. Therefore, targeting epigenetic mechanisms emerges as a promising strategy to prevent drug resistance. Previously, CRPCa cell lines resistant to Dtx and Cbz were generated to identify potential epigenetic targets that could overcome resistance. The Epigenetic Drug Library screen was conducted to uncover the reversing effects of epigenetic modifiers on resistance mechanism. In this thesis, the screen revealed Protein Arginine Methyltransferase 5 (PRMT5) as a re-sensitizer to taxane treatment. RNA sequencing analyses revealed that PRMT5 silencing led to the negative enrichment of four signaling pathways, including MYC, E2F, and G2/M. Indeed, MYC inhibition led to a stronger suppression of growth in resistant cells contrast to parental cells. Furthermore, the treatment of resistant cell lines with PRMT5 inhibitors induced cell cycle arrest in the G2/M phase, suggesting the restoration of taxane susceptibility. This effect was accompanied by an increase in apoptotic markers (Caspase 3/7 activation and Annexin-V staining). Pharmacological inhibition of PRMT5 reduced ABCB1 activity, as determined by the Calcein efflux assay, indicating that PRMT5 may be involved in an efflux-related mechanism. These results offered valuable insights into potential avenues for addressing taxane resistance in CRPCa treatment, paving the way for the development of more effective therapeutic strategies.