Li Jingxian, Shan Kun, Huang Wei, Su Qiang, Qi Yuanjiong, Zhang Zhihong, Zhu Jianqiang, Du E
Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Front Immunol. 2025 Jan 7;15:1432586. doi: 10.3389/fimmu.2024.1432586. eCollection 2024.
As an antibody-drug conjugate (ADC), disitamab vedotin (RC48) is a promising treatment targeting ERBB2 for locally advanced and metastatic bladder cancer (BLCA). However, the subtype heterogeneity of muscle-invasive bladder cancer (MIBC) often leads to different therapeutic outcomes. In our study, we aim to explore sensitivity differences and mechanisms of different molecular subtypes of MIBC to RC48 treatment and develop a strategy for combination therapy against cancer. Using large-scale mRNA expression profile datasets, Western blotting, and immunohistochemistry, we first found that ERBB2 is upregulated in the luminal type but downregulated in basal bladder cancer. In addition, luminal cells showed higher sensitivity to RC48 than basal cells. Basal cells with ERBB2 overexpression demonstrated increased sensitivity to RC48 and , indicating that ERBB2 expression mediates RC48's therapeutic efficacy against cancer. In basal or RC48-exposed luminal cells, the JAK/STAT3 pathway was highly enriched, suggesting that downregulation or pharmacological inhibition of ERBB2 leads to compensatory activation of this pathway. Silencing STAT3 increased the inhibitory efficacy of RC48. In addition, artesunate (ART, a STAT3 inhibitor) showed a synergistic effect with RC48 against basal bladder cancer both and . In summary, these findings provide a theoretical foundation for subsequent clinical trials combining RC48 and ART in MIBC based on molecular subtypes.
作为一种抗体药物偶联物（ADC），迪西他单抗维泊妥珠单抗（RC48）是一种有前景的针对局部晚期和转移性膀胱癌（BLCA）的ERBB2靶向治疗药物。然而，肌层浸润性膀胱癌（MIBC）的亚型异质性常常导致不同的治疗结果。在我们的研究中，我们旨在探索MIBC不同分子亚型对RC48治疗的敏感性差异及机制，并制定一种联合抗癌治疗策略。通过使用大规模mRNA表达谱数据集、蛋白质免疫印迹法和免疫组织化学，我们首先发现ERBB2在管腔型中上调，但在基底型膀胱癌中下调。此外，管腔型细胞对RC48的敏感性高于基底型细胞。ERBB2过表达的基底型细胞对RC48的敏感性增加，这表明ERBB2表达介导了RC48对癌症的治疗效果。在基底型或暴露于RC48的管腔型细胞中，JAK/STAT3通路高度富集，这表明ERBB2的下调或药理抑制会导致该通路的代偿性激活。沉默STAT3增加了RC48的抑制效果。此外，青蒿琥酯（ART，一种STAT3抑制剂）在体外和体内均显示出与RC48联合对基底型膀胱癌具有协同作用。总之，这些发现为后续基于分子亚型在MIBC中联合使用RC48和ART进行临床试验提供了理论基础。
