TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer
TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer
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DOI：
10.1073/pnas.1308587110
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发表时间：
2013-10-22
影响因子：
11.1
通讯作者：
Dehm, Scott M.
中科院分区：
文献类型：
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作者：
Nyquist, Michael D.;Li, Yingming;Dehm, Scott M.
雄激素受体（AR）靶基因指导前列腺上皮谱系（包括前列腺癌（PCa））的发育和存活。因此，抑制AR配体结合结构域（LBD）的内分泌疗法在治疗PCa中是有效的。AR转录重新激活是耐药性的核心，下一代内分泌疗法阿比特龙和恩杂鲁胺对AR重新靶向治疗去势抵抗性前列腺癌（CRPC）的疗效就证明了这一点。然而，对阿比特龙和恩杂鲁胺的耐药性限制了大多数男性的这种疗效，PCa仍然是男性癌症死亡的第二大原因。在这里，我们表明，AR基因重排CRPC组织的基础是一个完全雄激素依赖性，但AR依赖性，耐药机制。我们发现了CRPC组织中的基因内AR基因重排，我们使用转录激活因子样效应核酸酶（TALEN）介导的基因组工程对其进行了建模。该模型显示，这些AR基因重排阻断全长AR合成，但促进缺乏AR配体结合结构域的截短AR变体蛋白的表达。此外，这些AR变体蛋白保持了AR转录程序的组成性活性和CRPC生长表型，不依赖于全长AR或雄激素。这些研究结果表明，AR基因重排是一种独特的耐药机制，通过这种机制，AR转录活性可以与CRPC的内分泌调控脱钩。
Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa. AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism. We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand-binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens. These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC.