Purpose: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacological tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE. Experimental Design: TC is a transcriptional co-regulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence (IF) in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated. Results: Basal TC remained ‘immobile’ in the nucleus; administration of cyclin-dependent kinase inhibitors (CDKi) such as CGP60474 and dinaciclib mobilized TC. ‘Mobile’ TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC. Conclusions: The CDK inhibitor dinaciclib exhibited anti-tumorigenic properties both in vitro and in vivo in EHE models. Dinaciclib has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing dinaciclib for the treatment of EHE.

中文翻译：

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dinaciclib 抑制 CDK9 是上皮样血管内皮瘤的治疗脆弱性


目的：对于 TAZ-CAMTA1 (TC) 融合基因驱动的侵袭性上皮样血管内皮瘤 (EHE) 患者，尚无有效的治疗方案。在这里，我们的目的是了解使用药理学工具对 TC 的调节，并确定可用于治疗 EHE 的潜在漏洞。实验设计：TC是转录辅调节因子；我们假设，通过将 TC 转移到细胞质或通过降解，降低 TC 核水平的化合物将使 TC 的致癌性降低。在 EHE 肿瘤细胞系中使用免疫荧光 (IF) 监测 TC 定位。两个目标选择性文库用于鉴定减少 TC 在细胞核中定位的小分子。还评估了入围的命中影响细胞活力、细胞凋亡和肿瘤发生的能力。结果：Basal TC 在细胞核中保持“不动”；给予细胞周期蛋白依赖性激酶抑制剂 (CDKi)，例如 CGP60474 和 dinaciclib 来动员 TC。 “移动”TC在细胞核和细胞质之间穿梭；然而，它最终被蛋白酶体降解。这显着抑制了 TC 调节的转录物和细胞活力的水平，促进细胞凋亡，并减少了 EHE 同种异体移植模型中的转移灶面积。我们特别发现，抑制 CDK9（一种转录 CDK）会破坏 TC 的稳定性。结论：CDK 抑制剂 dinaciclib 在 EHE 模型中在体外和体内均表现出抗肿瘤特性。 Dinaciclib 已在临床试验中经过严格测试，并显示出可接受的毒性特征。因此，重新利用 dinaciclib 治疗 EHE 存在潜在的治疗窗口。