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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MSK Authors
  1. Charles L Sawyers
    199 Sawyers
  2. Anuradha Gopalan
    348 Gopalan
  3. Dana Elizabeth Rathkopf
    206 Rathkopf
  4. Brett Stewart Carver
    132 Carver
  5. Philip A Watson
    23 Watson
  6. Xuejun Jiang
    99 Jiang
  7. Wassim Abida
    108 Abida
  8. Xiaoping Chen
    5 Chen
  9. Zeda Zhang
    12 Zhang
  10. Ninghui   Mao
    15 Mao
  11. HuiYong   Zhao
    15 Zhao
  12. Chao Wu
    12 Wu
  13. Hsuan An Chen
    6 Chen
  14. Eugine Lee
    4 Lee
  15. Danielle Wai-pui Li
    12 Li
  16. Young Sun Lee
    10 Lee
  17. Eliot Laughlin Linton
    5 Linton
  18. Jose Mauricio Mota
    13 Mota
  19. Vianne Ran Gao
    4 Gao