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 language | English (US) |
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Pages (from-to) | 279-296.e9 |
Journal | Cancer Cell |
Volume | 38 |
Issue number | 2 |
DOIs | |
State | Published - Aug 10 2020 |
Keywords
- NRG1/neuregulin 1
- cancer-associated fibroblast
- drug resistance
- hormone therapy
- tumor microenvironment
ASJC Scopus subject areas
- Oncology
- Cancer Research