Acquired resistance to a drug treatment is a common problem across many cancers including prostate cancer (PCa) - one of the major factors for male mortality. The androgen receptor (AR) continues to be the main therapeutic PCa target and despite the success of modern targeted therapies such as enzalutamide, resistance to these drugs eventually develops. The AR has found many ways to adapt to treatments including overexpression and production of functional, constitutively active splice variants. However, of particular importance are point mutations in the ligand binding domain of the protein that convert anti-androgens into potent AR agonists. This mechanism appears to be especially prevalent with the AR in spite of some distant similarities to other hormone nuclear receptors. Despite the AR being one of the most studied and attended targets in cancer, those gain-of-function mutations in the receptor remain a significant challenge for the development of PCa therapies. This drives the need to fully characterize such mutations and to consistently screen PCa patients for their occurrence to prevent adverse reactions to anti-androgen drugs. Novel treatments should also be developed to overcome this resistance mechanism and more attention should be given to the possibility of similar occurrences in other cancers.

中文翻译：

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雄激素受体可塑性及其对前列腺癌治疗的意义。

在许多癌症中，包括对男性死亡率的主要因素之一，包括前列腺癌（PCa）在内，对药物治疗产生的抗药性是一个普遍的问题。雄激素受体（AR）仍然是PCa的主要治疗目标，尽管现代靶向治疗（例如恩杂鲁胺）取得了成功，但最终仍对这些药物产生了抗药性。AR发现了许多适应治疗的方法，包括过表达和产生功能性，组成型活性剪接变体。然而，尤为重要的是蛋白质的配体结合域中的点突变，其将抗雄激素转化为有效的AR激动剂。尽管与其他激素核受体有一些遥远的相似性，但这种机制似乎在AR中尤为普遍。尽管AR是癌症中研究最多，参与最广泛的靶标之一，但受体中的那些功能获得性突变仍然是PCa疗法发展的重大挑战。这就需要充分表征此类突变并持续筛查PCa患者的发生，以防止对抗雄激素药物产生不良反应。还应开发新的治疗方法以克服这种耐药机制，并应更多地关注其他癌症中类似情况的可能性。