Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

Autor: Anuradha Gopalan, Zeda Zhang, Charles L. Sawyers, Katia Manova-Todorova, Huiyong Zhao, Brett S. Carver, Dana E. Rathkopf, Jose Mauricio Mota, Steven P. Balk, Eugine Lee, Young Sun Lee, Chao Wu, Ping Mu, Wouter R. Karthaus, John Wongvipat, Ninghui Mao, Elisa de Stanchina, Menghan Liu, Vianne R. Gao, Xuejun Jiang, Xiaoping Chen, Wassim Abida, Danielle Choi, Mary-Ellen Taplin, Spencer D. Barnes, Philip A. Watson, Joshua W. Russo, Eliot Linton, Hsuan An Chen
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Cancer Research
medicine.drug_class
Antiandrogens
medicine.medical_treatment
Neuregulin-1
Kaplan-Meier Estimate
Mice
SCID
urologic and male genital diseases
Antiandrogen
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cancer-Associated Fibroblasts
Prostate
Cell Line
Tumor
medicine
Tumor Microenvironment
Animals
Humans
Neuregulin 1
Antiandrogen Therapy
Cells
Cultured
Cell Proliferation
Tumor microenvironment
biology
business.industry
Gene Expression Profiling
Prostatic Neoplasms
Androgen Antagonists
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
biology.protein
Cancer research
Hormone therapy
business
Zdroj: Cancer cell. 38(2)
ISSN: 1878-3686
Popis: Summary 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.
Databáze: OpenAIRE
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