文章：

以PRMT5为靶点的联合疗法用于伴有高频ATM和TP53突变的套细胞淋巴瘤

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations

原文发布日期：2023-02-17

DOI: 10.1038/s41408-023-00799-6

类型: Article

开放获取: 是

英文摘要：

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.
 

摘要翻译： 

套细胞淋巴瘤（MCL）治疗持续面临的挑战仍然是疾病复发和治疗耐药，尤其在携带ATM与TP53肿瘤抑制基因体细胞突变的患者中更为突出。这些突变会随着耐药性出现和疾病进展而不断累积，这与我们的OncoPrint分析结果一致——ATM与TP53改变在复发/难治性（R/R）MCL中最为常见。研究发现，蛋白质精氨酸甲基转移酶5（PRMT5）在R/R MCL中表达上调，且预示不良预后。PRMT5抑制剂在ATM和/或TP53突变的MCL小鼠模型及CD19靶向CAR-T细胞疗法耐药的模型中均显示出显著抗肿瘤效果。基因敲除PRMT5能有效抑制体内肿瘤生长。联合使用PRMT5抑制剂与ATR或CDK4抑制剂，在体外和体内实验中都表现出协同抗肿瘤效应。本研究为治疗高突变负荷的R/R MCL提供了一种靶向PRMT5协调的多重促癌过程的合理联合治疗策略。

原文链接：

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations