Culig Zoran
Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Curr Mol Biol Rep. 2017;3(4):230-235. doi: 10.1007/s40610-017-0079-1. Epub 2017 Oct 23.
Compensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in prostate cancer. After hydroxyflutamide and bicalutamide were used in therapy of prostate cancer over many years, novel anti-androgen enzalutamide showed improved clinical activity. However, enzalutamide resistance develops over a certain time period, and molecular mechanisms responsible for this process are heterogeneous.
As with other anti-androgens, these mechanisms include alterations of AR but also may be associated with overexpression of oncogenes which should be targeted by novel therapies. Androgen receptor splice variants have been frequently described in patients who developed enzalutamide resistance. Mutant AR F876L has been detected in patients who are resistant to enzalutamide. Glucocorticoid receptor overexpression has been observed in patient tissues and in pre-clinical models of enzalutamide resistance.
There is a heterogeneous picture of enzalutamide resistance in prostate cancer and, therefore, the development of appropriate post-enzalutamide treatment remains a challenge.
在前列腺癌中已确定雄激素消融或抗雄激素治疗后导致雄激素受体表达和活性增加的代偿机制。在使用羟基氟他胺和比卡鲁胺治疗前列腺癌多年后，新型抗雄激素药物恩杂鲁胺显示出更好的临床活性。然而，恩杂鲁胺耐药性会在一定时间段内出现，且导致这一过程的分子机制是异质性的。
与其他抗雄激素药物一样，这些机制包括雄激素受体的改变，但也可能与癌基因的过表达有关，而新型疗法应针对这些癌基因。在出现恩杂鲁胺耐药的患者中，经常会发现雄激素受体剪接变体。在对恩杂鲁胺耐药的患者中检测到了突变型雄激素受体F876L。在患者组织和恩杂鲁胺耐药的临床前模型中观察到糖皮质激素受体过表达。
前列腺癌中恩杂鲁胺耐药情况复杂，因此，开展合适的恩杂鲁胺后续治疗仍具挑战性。
