Therapeutic targeting MDR1 expression by RORγ antagonists resensitizes cross-resistant CRPC to taxane via coordinated induction of cell death programs

We report here that RORγ, a nuclear receptor family member, unexpectedly mediates MDR1/ABCB1 overexpression. RORγ plays an important role in controlling the functions of subsets of immune cells and has been an attractive target for autoimmune diseases. We found that its small-molecule antagonists are efficacious in re-sensitizing DTX and CTX cross-resistant CRPC cells and tumors to taxanes in both androgen receptor (AR)-positive and -negative models. Our mechanistic analyses revealed that combined treatment with RORγ antagonists and taxane elicited a robust synergy in killing the resistant cells, which involves a coordinated alteration of p53, Myc and E2F-controlled programs critical for both intrinsic and extrinsic apoptosis, survival and cell growth. Our results suggest that targeting RORγ with small-molecule inhibitors is a novel strategy for chemotherapy resensitization in tumors with MDR1 overexpression. A total of 4 samples were analyzed in this study. The study included one cell line C4-2B-TaxR. C4-2B-TaxR cells were cultured in medium and treated for 48 hours with control vehicle, RORgamma inhibitor SR2211 and/or chemotherapy drug docetaxel.