Systematic Evaluation for the Influences of the SOX17/Notch Receptor Family Members on Reversing Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells

Abstract

The treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the failure of androgen deprivation therapy (ADT); hence the search for other molecular therapeutic targets besides androgen receptor signaling is ongoing. This study systematically investigated the expression of SOX17 and Notch receptors in CRPC tissues and cells <i>in vitro</i>, showing that consistent clinical CRPC, SOX17/Notch1, and Notch4 were responsible for enzalutamide resistance in CRPC cells. The <i>γ</i> secretase inhibitors, BMS-708163, GSI-IX, PF-3084014, and RO4929097 abrogated the enzalutamide resistance by inhibiting Notch1 or/and Notch4 <i>in vitro</i>, with GSI-IX and RO4929097 being more effective than BMS-708163 and PF-3084014 in reliving bone metastasis <i>in vivo</i>. In conclusion, the Notch1 and Notch4 inhibitors GSI-IX and RO4929097 are promising therapeutic agents for the treatment of CRPC.