Kohli Manish, Ho Yeung, Hillman David W, Van Etten Jamie L, Henzler Christine, Yang Rendong, Sperger Jamie M, Li Yingming, Tseng Elizabeth, Hon Ting, Clark Tyson, Tan Winston, Carlson Rachel E, Wang Liguo, Sicotte Hugues, Thai Ho, Jimenez Rafael, Huang Haojie, Vedell Peter T, Eckloff Bruce W, Quevedo Jorge F, Pitot Henry C, Costello Brian A, Jen Jin, Wieben Eric D, Silverstein Kevin A T, Lang Joshua M, Wang Liewei, Dehm Scott M
Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Clin Cancer Res. 2017 Aug 15;23(16):4704-4715. doi: 10.1158/1078-0432.CCR-17-0017. Epub 2017 May 4.
Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3' terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31-12.2; = 0.02). AR-V9 may be an important component of therapeutic resistance in CRPC. .
雄激素受体（AR）变体AR-V7是一种不依赖配体的转录因子，可促进前列腺癌对AR靶向治疗产生耐药性。因此，目前正在努力制定监测和抑制去势抵抗性前列腺癌（CRPC）中AR-V7的策略。本研究的目的是了解其他AR变体是否可能与AR-V7共表达，并促进对AR靶向治疗的耐药性。我们利用完整AR mRNA异构体的互补短读长和长读长测序来表征CRPC模型中的AR表达。分别通过RNA测序和逆转录聚合酶链反应评估CRPC转移灶和循环肿瘤细胞中AR-V7和AR-V9 mRNA的共表达。用多克隆抗血清评估CRPC模型中AR-V9蛋白的表达。在一项针对78例开始使用雄激素合成抑制剂醋酸阿比特龙治疗的CRPC期患者的前瞻性临床试验中，进行多变量分析以测试转移组织中AR变体mRNA表达是否与12周无进展生存终点相关。AR-V9经常与AR-V7共表达。发现这两种AR变体都共享一个共同的3'末端隐蔽外显子，这使得AR-V9容易受到以前认为仅针对AR-V7的实验操作的影响。AR-V9促进前列腺癌细胞的非配体依赖性生长。CRPC转移灶中高AR-V9 mRNA表达可预测对醋酸阿比特龙的原发性耐药（风险比=4.0；95%置信区间，1.31-12.2；P=0.02）。AR-V9可能是CRPC治疗耐药的一个重要组成部分。
