Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, Leuven 3000, Belgium.
Urology, Department of Development and Regeneration, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.
Nat Rev Urol. 2014 Dec;11(12):712-6. doi: 10.1038/nrurol.2014.243. Epub 2014 Sep 16.
The majority of prostate cancers are hormone-dependent at diagnosis highlighting the central role of androgen signalling in this disease. Surprisingly, most forms of castration-resistant prostate cancer (CRPC) are still dependent on the androgen receptor (AR) for survival. Therefore, the advent of new AR-targeting drugs, such as enzalutamide, is certainly beneficial for the many patients with metastatic CRPC. Indeed, this compound provides a substantial survival benefit-but it is not curative. This Perspectives article describes the different ways through which cancer cells can become resistant to enzalutamide, such as AR truncation and other mutations, as well as by-pass of the AR dependence of prostate cancer cells through expression of the glucocorticoid receptor. The clinical relevance of these mechanisms and emerging questions concerning new therapeutic regimens in the treatment of metastatic CRPC are being discussed.
大多数前列腺癌在诊断时依赖于激素，这突出表明雄激素信号在这种疾病中的核心作用。令人惊讶的是，大多数去势抵抗性前列腺癌（CRPC）仍然依赖雄激素受体（AR）来存活。因此，新的 AR 靶向药物（如恩扎鲁胺）的出现肯定对许多转移性 CRPC 患者有益。事实上，这种化合物提供了显著的生存获益——但它不是治愈性的。本文观点描述了癌细胞对恩扎鲁胺产生耐药性的不同方式，如 AR 截断和其他突变，以及通过表达糖皮质激素受体绕过前列腺癌细胞对 AR 的依赖。正在讨论这些机制的临床相关性以及在治疗转移性 CRPC 方面新的治疗方案所产生的新问题。
