Etoposide and topoisomerase II inhibition for aggressive prostate cancer: data from a translational study.

Abstract Background. Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated limited activity in patients with metastatic castration-resistant prostate cancer (mCRPC). In our study, we investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. We also compared the activity of VP-16 with that of docetaxel, enzalutamide and olaparib. In the datasets analysis, we explored the prevalence and clinical significance of TOP2 genetic and transcriptomic alterations in mCRPC. Methods. Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Large scale datasets were analyzed in cBioportal and STRING was used for the functional enrichment analysis. Results. VP-16 was active in all PCa cell lines analyzed and this drug demonstrated increased activity in the aggressive PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Of note, the maintainment of antiandrogen treatment in bicalutamide-resistant MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. Compared to LNCaP, TOP2A was found to be overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients’ prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss. Conclusions. Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16. Further investigations are warranted to determine the role of TOP2A in mCRPC and to assess the efficacy of VP-16, alone or in combination with other agents, for the treatment of patients with mCRPC.Key points: · Etoposide is a chemotherapeutic agent that shows significant activity in preclinical models of prostate cancer and increased activity is observed in the most aggressive cells.· Overexpression of topoisomerase II alfa and decreased functionality of the androgen receptor signaling seem to be associated with response to etoposide.· Specific patients with castration-resistant prostate cancer could benefit from etoposide treatment, alone or in combination with other agents.