Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.

Abstract

Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.

• Authors: Zeda Zhang, Wouter R Karthaus, Young Sun Lee, Vianne R Gao, Chao Wu, Joshua W Russo, Menghan Liu, Jose Mauricio Mota, Wassim Abida, Eliot Linton, Eugine Lee, Spencer D Barnes, Hsuan-An Chen, Ninghui Mao, John Wongvipat, Danielle Choi, Xiaoping Chen, Huiyong Zhao, Katia Manova-Todorova, Elisa de Stanchina, Mary-Ellen Taplin, Steven P Balk, Dana E Rathkopf, Anuradha Gopalan, Brett S Carver, Ping Mu, Xuejun Jiang, Philip A Watson, Charles L Sawyers
• Journal: Cancer cell (Cancer Cell) Vol. 38 Issue 2 Pg. 279-296.e9 (08 10 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 32679108 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Androgen Antagonists
• NRG1 protein, human
• Neuregulin-1

Topics

• Androgen Antagonists (pharmacology)
• Animals
• Cancer-Associated Fibroblasts (drug effects, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Cells, Cultured
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Kaplan-Meier Estimate
• Male
• Mice, SCID
• Neuregulin-1 (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, prevention & control)
• Tumor Microenvironment (drug effects, genetics)
• Xenograft Model Antitumor Assays (methods)