Therapeutic Targeting of MDR1 Expression by RORγ Antagonists Resensitizes Cross-Resistant CRPC to Taxane via Coordinated Induction of Cell Death Programs
Abstract
Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1)–encoded multidrug resistance protein 1 (MDR1) constitutes a major mechanism of cancer drug resistance including docetaxel (DTX) and cabazitaxel (CTX) resistance in castration-resistant prostate cancer (CRPC). However, no therapeutics that targets MDR1 is available at clinic for taxane sensitization. We report here that retinoic acid receptor-related orphan receptor γ (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 resensitizing DTX and CTX cross-resistant CRPC cells and tumors to taxanes in both androgen receptor–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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2020
- Source ID
- 10.1158/1535-7163.mct-19-0327
Entities
People
- Allen C Gao
- Chengfei Liu
- Christopher P Evans
- Christopher Z. Chen
- Fangjian Zhou
- Hong-Wu Chen
- Yongqiang Wang
- Zenghong Huang
Organizations
- National Cancer Institute
- National Institutes of Health
- Sun Yat-sen University
- University of California, Davis