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研究揭示前列腺癌对抗雄激素治疗产生耐药的机制
作者:小柯机器人 发布时间:2020/7/17 17:30:03

美国斯隆·凯特琳纪念癌症中心Charles L. Sawyers和蒋学军研究组合作发现,肿瘤微环境中的神经调节蛋白1(NRG1)促进前列腺癌抗雄激素耐药性的产生。这一研究成果在线发表在2020年7月16日的《癌细胞》上。

研究人员发现,与癌症相关的成纤维细胞(CAF)可以在小鼠模型和前列腺类器官培养物中促进抗雄激素耐药性。研究人员确定CAF上清液中的NRG1通过激活HER3促进肿瘤细胞的耐药性。使用临床级别的抗体对NRG1 / HER3通路进行药理学阻断可以在体外和体内使肿瘤对激素治疗重新敏感。

此外,患有去势抵抗性前列腺癌且肿瘤NRG1活性增强的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抵抗的旁分泌机制,该机制可通过使用可用的靶向疗法进行临床干预。

据悉,尽管研发了第二代抗雄激素药,但激素治疗的耐药性仍是治疗晚期前列腺癌的主要难题。

附:英文原文

Title: Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer

Author: 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

Issue&Volume: 2020-07-16

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.

DOI: 10.1016/j.ccell.2020.06.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30309-3

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx