Yu Ziyang, Chen Sen, Sowalsky Adam G, Voznesensky Olga S, Mostaghel Elahe A, Nelson Peter S, Cai Changmeng, Balk Steven P
Authors' Affiliations: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; and Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
Clin Cancer Res. 2014 Mar 15;20(6):1590-600. doi: 10.1158/1078-0432.CCR-13-1863. Epub 2014 Jan 21.
Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer that progresses after castration (castration-resistant prostate cancer; CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.
Prostate cancer xenografts were examined to identify mechanism of progression after castration and abiraterone.
AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR coregulators. In contrast, mRNA encoding full-length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared with xenografts before castration, with an increase in AR-V7 relative to AR-FL. This shift toward AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.
AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand-binding domain.
在去势后进展的前列腺癌（去势抵抗性前列腺癌；CRPC）以及随后使用阿比特龙（一种进一步抑制雄激素合成的CYP17A1抑制剂）治疗后，介导雄激素受体（AR）重新激活的机制仍不清楚。
对前列腺癌异种移植模型进行研究，以确定去势和阿比特龙治疗后的进展机制。
阿比特龙耐药的VCaP异种移植模型中的AR重新激活与肿瘤内雄激素的恢复或AR共调节因子的改变无关。相反，与去势前的异种移植模型相比，编码全长AR（AR-FL）和一种组成型活性剪接变体（AR-V7）的mRNA增加，且AR-V7相对于AR-FL有所增加。这种向AR-V7的转变是由于一种反馈机制，即雄激素结合的AR刺激那些相对于AR-FL转录本抑制AR-V7生成的蛋白质的表达。然而，尽管AR-V7 mRNA有所增加，但在耐药的VCaP异种移植模型和CRPC临床样本中，相对于AR-FL而言，它仍然是一种次要转录本（<1%）。在去势抵抗性VCaP异种移植模型和雄激素剥夺的VCaP细胞中，AR-V7蛋白表达相对于AR-FL同样较低，但AR-V7 siRNA进一步抑制了这些后者细胞中较弱的基础AR活性。
这些低水平的AR-V7不足以恢复AR活性，但其在雄激素剥夺后迅速诱导，使肿瘤能够保留基础AR活性，这可能是生存所必需的，直到出现更有效的激活AR的机制。靶向AR剪接变体的药物与靶向AR配体结合域的疗法联合使用时，在极早期使用可能最有效。
