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Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

Zeda Zhang1, Wouter R Karthaus2, Young Sun Lee2

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA.

Cancer Cell
|July 18, 2020
PubMed

Insights

Cancer-associated fibroblasts promote antiandrogen resistance in prostate cancer via NRG1 signaling. Blocking this pathway re-sensitizes tumors and may improve treatment response in patients.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Acquired resistance to antiandrogen therapy is a significant challenge in advanced prostate cancer treatment.
  • Understanding the mechanisms driving this resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of cancer-associated fibroblasts (CAFs) in promoting antiandrogen resistance in prostate cancer.
  • To identify specific molecular pathways involved in CAF-mediated resistance.
  • To evaluate the therapeutic potential of targeting these pathways.

Main Methods:

  • Utilized mouse models and prostate organoid cultures to study antiandrogen resistance.
  • Analyzed CAF supernatant for factors promoting resistance.
  • Investigated the neuregulin 1 (NRG1)/HER3 signaling axis.
  • Tested the efficacy of NRG1/HER3 blocking antibodies in vitro and in vivo.
  • Correlated tumor NRG1 activity with patient response to antiandrogen therapy.

Main Results:

  • CAFs were found to promote antiandrogen resistance in prostate cancer models.
  • Neuregulin 1 (NRG1) in CAF supernatant activates HER3 in tumor cells, driving resistance.
  • Pharmacological blockade of the NRG1/HER3 axis re-sensitized tumors to hormone deprivation.
  • Increased tumor NRG1 activity in patients correlated with poorer response to second-generation antiandrogens.

Conclusions:

  • CAFs confer antiandrogen resistance in prostate cancer through a paracrine NRG1/HER3 signaling mechanism.
  • Targeting the NRG1/HER3 axis with blocking antibodies offers a potential therapeutic strategy.
  • This approach shows promise for overcoming resistance and improving outcomes in castration-resistant prostate cancer.
Keywords:
NRG1/neuregulin 1cancer-associated fibroblastdrug resistancehormone therapytumor microenvironment

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