Valle Shelley, Sharifi Nima
Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Endocrinology. 2021 Sep 1;162(9). doi: 10.1210/endocr/bqab132.
In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through the androgen receptor (AR), the primary driver of prostate cancer, some malignancies are able take advantage of the closely related glucocorticoid receptor (GR). Escape from AR dependency often involves a simple functional switch from 1 steroid receptor to another. Recent research efforts have outlined the mechanism enabling this switch, which involves alterations in glucocorticoid metabolism that occur with antiandrogen therapy to increase tumor tissue glucocorticoids and enable GR signaling. Targeting this mechanism pharmacologically by blocking hexose-6-phosphate dehydrogenase shows promise in normalizing glucocorticoid metabolism and restoring responsiveness to antiandrogen therapy. This perspective reviews what we have learned about this resistance mechanism, examines potential implications, and considers how this knowledge might be harnessed for therapeutic benefit.
在转移性前列腺癌的治疗中，对激素疗法的耐药性是一个主要障碍。通过抗雄激素疗法抑制雄激素受体（AR）介导的雄激素信号传导（AR是前列腺癌的主要驱动因素），一些恶性肿瘤能够利用密切相关的糖皮质激素受体（GR）。从AR依赖性中逃逸通常涉及从一种类固醇受体到另一种类固醇受体的简单功能转换。最近的研究工作已经阐明了促成这种转换的机制，该机制涉及抗雄激素治疗时发生的糖皮质激素代谢改变，从而增加肿瘤组织中的糖皮质激素并激活GR信号传导。通过阻断6-磷酸己糖脱氢酶从药理学上靶向这一机制，有望使糖皮质激素代谢正常化并恢复对抗雄激素治疗的反应性。本文综述了我们对这种耐药机制的认识，探讨了潜在影响，并考虑如何利用这些知识实现治疗益处。
