The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2–Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2–Stat5 signaling was assessed in vivo in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2–Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2–Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2–Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.

中文翻译：

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恩杂鲁胺诱导的前馈信号回路促进抗治疗前列腺癌的生长，为 Jak2 抑制剂提供可利用的分子靶点

第二代抗雄激素 enzalutamide 被批准用于去势抵抗性前列腺癌 (CRPC) 并靶向 CRPC 中的雄激素受体 (AR) 活性。尽管最初有临床活动，但对恩杂鲁胺的获得性耐药迅速出现，大多数患者发展为终末期疾病。先前的工作已将 Stat5 确立为前列腺癌生长的有效诱导剂。在这里，我们研究了 Jak2-Stat5 信号在前列腺癌对恩杂鲁胺耐药中的重要性。在恩杂鲁胺治疗前后，在前列腺癌细胞、异种移植肿瘤和临床前列腺癌中评估了 Jak2 和 Stat5 mRNA、蛋白质和活化的水平。Jak2 和 Stat5 被使用慢病毒 shRNA 或药理学抑制剂的基因敲低抑制。在携带前列腺癌异种移植肿瘤的小鼠体内评估原发性和恩杂鲁胺耐药前列腺癌对 Jak2-Stat5 信号传导药物抑制剂的反应性。在肿瘤外植体培养中恩杂鲁胺离体后，测试了患者来源的前列腺癌对作为二线治疗的 Stat5 阻断剂的反应性。Enzalutamide 配体 AR 在前列腺癌中诱导持续的 Jak2-Stat5 磷酸化，导致正前馈环的形成，其中激活的 Stat5 反过来诱导 Jak2 mRNA 和蛋白质水平，有助于进一步激活 Jak2。从机制上讲，恩杂鲁胺配体的 AR 通过涉及 Jak2 特异性磷酸酶的过程诱导 Jak2 磷酸化。Stat5 在恩杂鲁胺治疗期间促进了前列腺癌的生长。Jak2-Stat5 抑制诱导前列腺癌细胞死亡和患者来源的前列腺癌在恩杂鲁胺治疗后幸存下来，并阻止小鼠中恩杂鲁胺耐药的肿瘤生长。这项工作引入了一个新概念，即过度激活的 Jak2-Stat5 信号在恩杂鲁胺耐药的前列腺癌中的关键作用，在临床开发中很容易被 Jak2 抑制剂靶向。