Tumor microenvironment-derived NRG1 promotes antiandrogen resistance in prostate cancer Journal Article


Authors: 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.; de Stanchina, E.; Taplin, M. E.; Balk, S. P.; Rathkopf, D. E.; Gopalan, A.; Carver, B. S.; Mu, P.; Jiang, X.; Watson, P. A.; Sawyers, C. L.
Article Title: 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. © 2020 The Authors Zhang et al. find that cancer-associated fibroblasts promote antiandrogen resistance in prostate cancer by secreting NRG1 to activate HER3 signaling in prostate cancer cells. Blockade of the NRG1/HER3 axis can re-sensitize prostate cancer models to antiandrogen therapy. © 2020 The Authors
Keywords: controlled study; protein phosphorylation; treatment outcome; human cell; nonhuman; comparative study; follow up; mouse; gene expression; protein targeting; animal experiment; animal model; drug resistance; protein tyrosine kinase; phosphatidylinositol 3 kinase; cancer resistance; prostate cancer; gleason score; alpha smooth muscle actin; mammalian target of rapamycin; androgen deprivation therapy; hormone therapy; vimentin; tumor microenvironment; abiraterone; cancer associated fibroblast; neu differentiation factor; enzalutamide; antiandrogen therapy; cancer-associated fibroblast; human; male; priority journal; article; lncap cell line; nrg1/neuregulin 1
Journal Title: Cancer Cell
Volume: 38
Issue: 2
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2020-08-10
Start Page: 279
End Page: 296.e9
Language: English
DOI: 10.1016/j.ccell.2020.06.005
PUBMED: 32679108
PROVIDER: scopus
PMCID: PMC7472556
DOI/URL:
Notes: Article -- Export Date: 1 September 2020 -- Source: Scopus
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  1. Charles L Sawyers
    226 Sawyers
  2. Anuradha Gopalan
    417 Gopalan
  3. Dana Elizabeth Rathkopf
    273 Rathkopf
  4. Brett Stewart Carver
    143 Carver
  5. Philip A Watson
    26 Watson
  6. Xuejun Jiang
    121 Jiang
  7. Wassim Abida
    157 Abida
  8. Xiaoping Chen
    11 Chen
  9. Zeda Zhang
    18 Zhang
  10. Ninghui   Mao
    19 Mao
  11. HuiYong   Zhao
    26 Zhao
  12. Chao Wu
    21 Wu
  13. Hsuan An Chen
    9 Chen
  14. Eugine Lee
    4 Lee
  15. Danielle Wai-pui Li
    12 Li
  16. Young Sun Lee
    11 Lee
  17. Eliot Laughlin Linton
    5 Linton
  18. Jose Mauricio Mota
    13 Mota
  19. Vianne Ran Gao
    12 Gao