Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.

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.

Cancer cell. 2020 Jun 23 [Epub ahead of print]

Zeda Zhang, Wouter R Karthaus, Young Sun Lee, Vianne R Gao, Chao Wu, Joshua W Russo, Menghan Liu, Jose Mauricio Mota, Wassim Abida, Eliot Linton, Eugine Lee, Spencer D Barnes, Hsuan-An Chen, Ninghui Mao, John Wongvipat, Danielle Choi, Xiaoping Chen, Huiyong Zhao, Katia Manova-Todorova, Elisa de Stanchina, Mary-Ellen Taplin, Steven P Balk, Dana E Rathkopf, Anuradha Gopalan, Brett S Carver, Ping Mu, Xuejun Jiang, Philip A Watson, Charles L Sawyers

Human 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., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Hematology-Oncology Division, Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Bioinformatics Core Facility of the Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA., Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA., Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA., Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA. Electronic address: ., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA. Electronic address: ., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20185, USA. Electronic address: .