Neuroendocrine prostate cancer drivers SOX2 and BRN2 confer differential responses to imipridones ONC201, ONC206, and ONC212 in prostate cancer cell lines.

Objectives: Prostate cancer (PCa) is a leading cause of cancer death in men worldwide. Approximately 30% of castrate-resistant PCa becomes refractory to therapy due to neuroendocrine differentiation (NED) that is present in <1% of de-novo tumors. First-in-class imipridone ONC201/TIC10 therapy has shown clinical activity against midline gliomas, neuroendocrine tumors, and PCa. We explored whether NED promotes sensitivity to imipridones ONC201 and ONC206 by inducibly overexpressing SOX2 and BRN2, well-known neuroendocrine drivers.

Methods: Inducible SOX2 or BRN2 systems were cloned into human PCa cell lines LNCaP and DU145. Inducible cell lines were characterized based on protein expression, morphology, and migration. The sensitivity of the inducible cell lines to imipridone therapy was determined by viability, cell growth, or clonogenic assays.

Results: Slight protection from ONC201 or ONC206 with SOX2 and BRN2 overexpression was observed in the inducible LNCaP cells but not in the DU145 cells. At 2 months, there was an apparent increase in CLpP expression in LNCaP SOX2-overexpressing cells, though this did not confer enhanced sensitivity to ONC201. DU145 SOX2-overexpressing cells had a significantly reduced ONC201 sensitivity than DU145 control cells.

Conclusions: The results suggest that treatment of castrate-resistant prostate cancer by imipridones may not be substantially affected by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.