Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

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 StanchinaMary Ellen Taplin, Steven P. Balk, Dana E. Rathkopf, Anuradha Gopalan, Brett S. Carver, Ping Mu, Xuejun Jiang, Philip A. Watson, Charles L. Sawyers

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)279-296.e9
JournalCancer Cell
Volume38
Issue number2
DOIs
StatePublished - Aug 10 2020

Keywords

  • cancer-associated fibroblast
  • drug resistance
  • hormone therapy
  • NRG1/neuregulin 1
  • tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Zhang, Z., Karthaus, W. R., Lee, Y. S., Gao, V. R., Wu, C., Russo, J. W., Liu, M., Mota, J. M., Abida, W., Linton, E., Lee, E., Barnes, S. D., Chen, H. A., Mao, N., Wongvipat, J., Choi, D., Chen, X., Zhao, H., Manova-Todorova, K., ... Sawyers, C. L. (2020). Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. Cancer Cell, 38(2), 279-296.e9. https://doi.org/10.1016/j.ccell.2020.06.005