Therapeutic Targeting of MDR1 Expression by RORγ Antagonists Resensitizes Cross-Resistant CRPC to Taxane via Coordinated Induction of Cell Death Programs

Yongqiang Wang, Zenghong Huang, Christopher Z. Chen, Chengfei Liu, Christopher P. Evans, Allen C. Gao, Fangjian Zhou, Hong Wu Chen

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)364-374
Number of pages11
JournalMolecular cancer therapeutics
Volume19
Issue number2
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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