MiR26a Reverses Enzalutamide Resistance in a Bone-Tumor Targeted System with an Enhanced Effect on Bone Metastatic CRPC

Abstract

Abstract Resistance to androgen receptor (AR) inhibitors including enzalutamide (ENZ) as well as bone metastasis are major challenges for castration-resistant prostate cancer (CRPC) treatment. In this study, we identified that miR26a can restore the Enz sensitivity and inhibit bone metastatic CRPC. To achieve the highest combination effect of miR26a and Enz, we developed a cancer-targeted nano-system (Bm@PT/Enz-miR26a) using bone marrow mesenchymal stem cell (BMSC) membrane and T140 peptide to co-deliver Enz and miR26a. The in vitro/in vivo results demonstrated that miR26a can reverse Enz resistance and synergistically shrink tumor growth, invasion, and metastasis (especially secondary metastasis) in both subcutaneous and bone metastatic CRPC mouse models. We also found that EZH2/SFRP1/WNT5A axis may in involved in this role. These findings open new avenues for the treatment of bone metastatic and Enz resistant CRPC.