Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

Cancer Cell. 2020 Aug 10;38(2):279-296.e9. doi: 10.1016/j.ccell.2020.06.005. Epub 2020 Jul 16.

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.

Keywords: NRG1/neuregulin 1; cancer-associated fibroblast; drug resistance; hormone therapy; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Animals
  • Cancer-Associated Fibroblasts / drug effects
  • Cancer-Associated Fibroblasts / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / 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*
  • Neuregulin-1 / metabolism
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / prevention & control
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics*
  • Xenograft Model Antitumor Assays / methods

Substances

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