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.

尽管开发了第二代抗雄激素药物，但对激素治疗的获得性耐药仍然是治疗晚期前列腺癌的主要挑战。我们发现癌症相关成纤维细胞 (CAF) 可以促进小鼠模型和前列腺类器官培养物中的抗雄激素耐药性。我们在 CAF 上清液中鉴定出神经调节蛋白 1 (NRG1)，它通过激活 HER3 促进肿瘤细胞的耐药性。使用临床级阻断抗体对 NRG1/HER3 轴的药理学阻断使肿瘤在体外和体内对激素剥夺重新敏感. 此外，肿瘤NRG1活性增加的去势抵抗性前列腺癌患者对第二代抗雄激素治疗的反应较差。这项工作揭示了前列腺癌中抗雄激素抗性的旁分泌机制，可以使用现有的靶向疗法进行临床测试。