文章：

使用VLX1570共同抑制去泛素化酶USP14和UCHL5对伊布替尼或硼替佐米耐药的华氏巨球蛋白血症肿瘤细胞具有致死作用

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells

原文发布日期：2016-11-04

DOI: 10.1038/bcj.2016.93

类型: Original Article

开放获取: 是

英文摘要：

The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.

摘要翻译： 

华氏巨球蛋白血症（WM）肿瘤细胞的存活依赖于异常的B细胞受体（BCR）和MYD88信号传导。WM细胞通过上调蛋白酶体功能来维持BCR驱动的生长，同时保持细胞内稳态。临床上采用两种治疗策略通过伊布替尼（靶向BTK/MYD88节点）和硼替佐米（靶向20S蛋白酶体）来破坏这些互补但相互排斥的WM生存通路。尽管这两种药物均取得疗效，但WM患者最终会产生治疗耐药性，这凸显了WM细胞的适应可塑性，也表明开发新疗法的必要性。本文针对去泛素化酶（DUB）抑制剂VLX1570——一种靶向泛素特异性蛋白酶14（USP14）和泛素羧基末端水解酶L5（UCHL5）的新型小分子抑制剂——的抗WM活性提供了全面的临床前研究报告。这两种DUB均位于19S蛋白酶体帽中，VLX1570通过抑制其活性，在硼替佐米或伊布替尼耐药的WM细胞中诱导快速且肿瘤特异性的凋亡。值得注意的是，用VLX1570处理WM细胞可下调BCR相关元件BTK、MYD88、NFATC、NF-κB和CXCR4，其中CXCR4功能失调与伊布替尼耐药相关。在WM异种移植小鼠模型中，与溶剂对照组相比，VLX1570治疗组小鼠肿瘤负荷减轻且生存期延长（P=0.0008）。总体而言，我们的研究证明了VLX1570靶向USP14/UCHL5在耐药性WM治疗中的重要价值，并展现出较高的临床转化潜力。

原文链接：

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells