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

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

doi:10.1158/1535-7163.mct-19-0327

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.

Highlights

Prostate cancer is still one of the leading causes of cancer-related death among men in the United States [1]
Most patients initially respond to androgen-deprivation therapy (ADT), their tumors eventually become resistant to ADT and the disease progresses to metastatic castration-resistant prostate cancer
multidrug resistance protein 1 (MDR1)/ATP-binding cassette subfamily B member 1 (ABCB1) overexpression is controlled by receptor g (RORg) Because MDR1/ABCB1 overexpression is the major mechanism of taxane cross-resistance of C4-2B-TaxR cells [23, 31], we investigated whether RORg regulated MDR1 expression in those cells

Summary

Introduction

Prostate cancer is still one of the leading causes of cancer-related death among men in the United States [1]. Most patients initially respond to androgen-deprivation therapy (ADT), their tumors eventually become resistant to ADT and the disease progresses to metastatic castration-resistant prostate cancer Docetaxel (DTX) and cabazitaxel (CTX) are microtubule-stabilizing taxane chemotherapy agents. They exert their therapeutic effects mainly through microtubule disassembly blockade–induced G2–M cell-cycle arrest and induction of apoptosis. Other effects including suppression of the expression or function of the androgen receptor (AR) have been described for DTX [4,5,6,7,8,9]. DTX and CTX are currently used as the first- and second-line treatment for mCRPC. Only about half of patients with mCRPC respond to DTX or CTX, and those who initially respond will eventually become resistant to them [4, 7]

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Conclusion