Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance.
Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance.
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DOI：
10.1158/1078-0432.ccr-17-0017
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Dehm SM
中科院分区：
文献类型：
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作者：
Kohli M;Ho Y;Hillman DW;Van Etten JL;Henzler C;Yang R;Sperger JM;Li Y;Tseng E;Hon T;Clark T;Tan W;Carlson RE;Wang L;Sicotte H;Thai H;Jimenez R;Huang H;Vedell PT;Eckloff BW;Quevedo JF;Pitot HC;Costello BA;Jen J;Wieben ED;Silverstein KAT;Lang JM;Wang L;Dehm SM
雄激素受体（AR）变体AR-V7是一种配体非依赖性转录因子，可促进前列腺癌对AR靶向治疗的耐药性。因此，正在努力开发用于监测和抑制去势抵抗性前列腺癌（CRPC）中的AR-V7的策略。这项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亚型的互补短读和长读测序来表征CRPC模型中的AR表达。分别通过RNA-seq和RT-PCR评估CRPC转移和循环肿瘤细胞中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。在一项前瞻性临床试验中，对78例开始接受雄激素合成抑制剂醋酸阿比特龙治疗的CRPC期患者进行了多变量分析，以检测转移组织中AR变体mRNA表达是否与12周无进展生存期终点相关。AR-V9经常与AR-V7共表达。发现两种AR变体种类共享共同的3'末端隐蔽外显子，这使得AR-V9对先前认为独特地靶向AR-V7的实验操作敏感。AR-V9促进前列腺癌细胞的配体非依赖性生长。CRPC转移灶中AR-V9 mRNA的高表达预示着对醋酸阿比特龙的原发性耐药（HR = 4.0，95%CI = 1.31-12.2，P = 0.02）。AR-V9可能是CRPC治疗耐药的重要组成部分。
Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are underway 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 co-expressed 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. Co-expression 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 co-expressed 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% CI = 1.31–12.2, P = 0.02). AR-V9 may be an important component of therapeutic resistance in CRPC.