文章：

布鲁顿酪氨酸激酶抑制可恢复由BCL10功能获得性突变体驱动的多药耐药弥漫性大B细胞淋巴瘤对维奈托克的敏感性

Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax

原文发布日期：2025-02-02

DOI: 10.1038/s41408-025-01214-y

类型: Article

开放获取: 是

英文摘要：

Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.
 

摘要翻译： 

弥漫大B细胞淋巴瘤作为最常见的淋巴瘤类型，其各异的致病机制使得精准医学治疗面临挑战。尽管前线联合化学免疫疗法可能治愈该病，但即使近期免疫治疗取得进展，复发或难治性患者的预后依然不佳。基于近期研究发现BCL10信号蛋白的功能获得性突变是导致布鲁顿酪氨酸激酶抑制剂耐药的主要驱动因素，本研究进一步揭示突变BCL10驱动的淋巴瘤对多种其他药物类别同样耐药。这表明亟需建立基于机制的治疗策略，以克服这些"不可成药"的BCL10突变体——它们能稳定NF-κB活化上游不依赖BTK的信号丝聚合体。BCL10突变体促进细胞因子强化的淋巴瘤发生正反馈循环，不仅激活NF-κB通路，更汇聚于致癌转录因子的广泛激活。抗凋亡基因的上调增加了线粒体膜电位，构成多药耐药的基础。BCL2、BCL2L1（BCL-XL）和BCL2A1（BFL1）表达升高导致维奈托克耐药，但强效非共价BTK抑制剂吡托布鲁替尼可逆转此效应。维奈托克联合吡托布鲁替尼在体外和体内实验中均能协同克服耐药并有效杀伤BCL10突变淋巴瘤。因此，即使BCL10信号复合体的下游激活能独立活化NF-κB，BTK在保护DLBCL免于凋亡方面仍发挥着关键作用。

原文链接：

Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors driven by BCL10 gain-of-function mutants to venetoclax