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STUDY PROTOCOL article

Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1432586
This article is part of the Research Topic Antibody-Drug Conjugate Use in GU Malignancies View all 6 articles

The combination treatment of RC48 and STAT3 inhibitor acts as a promising therapeutic strategy in basal bladder cancer

Provisionally accepted
Jingxian Li Jingxian Li *Kun Shan Kun Shan Wei Huang Wei Huang Qiang Su Qiang Su Yuanjiong Qi Yuanjiong Qi Zhihong Zhang Zhihong Zhang Jianqiang Zhu Jianqiang Zhu E Du E Du
  • Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China

The final, formatted version of the article will be published soon.

    As a type of antibody-drug conjugate (ADC), Disitamab Vedotin (RC48) was a promising treatment method targeting ERBB2 for locally advanced and metastatic bladder cancer (BLCA). However, subtype heterogeneity of muscular-invasive bladder cancer (MIBC) often causes different therapeutic outcomes. In our study, we aim to explore sensitivity differences and mechanisms of different molecular subtypes of MIBC for RC48 treatment and excavate a strategy of combination treatment against cancer. Through large-scale mRNA expression profile datasets, western blot, and immunohistochemistry, we first found ERBB2 is up-regulated in luminal type but down-regulated in basal bladder cancer. In addition, luminal cells showed a higher sensitivity to RC48 than basal cells. The basal cells with ERBB2 overexpression represent an increased sensitivity to RC48 in vitro and vivo, indicating that ERBB2 expression mediates RC48's therapeutic efficacy against cancer. In basal or RC48-exposed luminal cells, JAK/STAT3 pathways showed a high enrichment, implicating down-regulation or pharmacological inhibition of ERBB2 causes compensatory activation of this pathway. Silencing STAT3 could increase the inhibition efficacy of RC48. In addition, artesunate (ART, STAT3 inhibitor) showed a synergistic effect with RC48 against basal bladder cancer in vitro and vivo. In summary, these findings provided a theoretical foundation for subsequent clinical trials of combining RC48 and ART in MIBC based on the molecular subtypes.

    Keywords: RC48-ADC, MIBC, Artesunate, Molecular subtypes, targeted therapy

    Received: 14 May 2024; Accepted: 02 Dec 2024.

    Copyright: © 2024 Li, Shan, Huang, Su, Qi, Zhang, Zhu and Du. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jingxian Li, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.