大多数肌层浸润性膀胱癌（MIBC）患者无法通过铂类化疗获得治愈。核因子kappaB轻链激活增强子（NF-κB）的上调是化疗耐药的主要机制，这表明其药理抑制可能增加铂类药物的疗效。本研究调查了两个患者队列中的NF-κB信号传导。使用肿瘤基因组图谱（TCGA）相关分析了NF-κB信号传导与患者生存的关系。通过体外实验测试了顺铂加NF-κB抑制剂二甲基氨基巴瑟诺利德（DMAPT）与顺铂或DMAPT单独的疗效。使用异种移植和免疫能力完好的MIBC小鼠模型进行了体内研究。原有未接受铂类药物治疗的肌层浸润性膀胱癌表现为持续性NF-κB信号传导，并且与TCGA患者的疾病特异性生存率下降相关。化疗上调了NF-κB信号传导和与耐药有关的基因，包括SPHK1、PLAUR和SERPINE1。在小鼠实验中，DMAPT显著提高了两个模型中顺铂的疗效。与单独使用顺铂相比，该组合能保护体重、肾功能和形态，减轻肌肉疲劳和IL-6血清水平，并且未加重免疫血液毒性。该资料为将NF-κB抑制与基于铂类药物的化疗相结合，并在MIBC患者中进行临床试验提供了依据。本文受版权保护，版权所有。

Most patients with muscle-invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up-regulation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF-κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF-κB signaling and patient survival. The efficacy of cisplatin plus the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum-naive claudin-low MIBC showed constitutive NF-κB signaling and this was associated with reduced disease-specific survival in TCGA patients. Chemotherapy up-regulated NF-κB signaling and chemoresistance-associated genes, including SPHK1, PLAUR and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function and morphology, reduced muscle fatigue and IL-6 serum levels, and did not aggravate immuno-hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF-κB inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.This article is protected by copyright. All rights reserved.