2. Academic Validation
  3. A potential strategy for bladder cancer treatment: inhibiting autophagy to enhance antitumor effects of Nectin-4-MMAE

A potential strategy for bladder cancer treatment: inhibiting autophagy to enhance antitumor effects of Nectin-4-MMAE

  • Cell Death Dis. 2024 Apr 25;15(4):293. doi: 10.1038/s41419-024-06665-y.
Yichen Wang 1,  Yanyang Nan 2,  Chunguang Ma 1,  Xiaolin Lu 1,  Qian Wang 2,  Xiting Huang 2,  Wenjing Xue 2,  Jiajun Fan 2,  Dianwen Ju 3,  Dingwei Ye 4,  Xuyao Zhang 5
Affiliations

Affiliations

  • 1 Department of Urology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 2 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, Shanghai, 201203, China.
  • 3 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, Shanghai, 201203, China. dianwenju@fudan.edu.cn.
  • 4 Department of Urology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. dwyeli@163.com.
  • 5 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, Shanghai, 201203, China. xuyaozhang@fudan.edu.cn.
PMID: 38664366 DOI: 10.1038/s41419-024-06665-y
Abstract

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial Cancer. During the course of this study, we identified that Autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder Cancer. Nectin-4-MMAE rapidly internalized into bladder Cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated Apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder Cancer cells treated with Nectin-4-MMAE, which suggested Autophagy was activated by Nectin-4-MMAE. Furthermore, Autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting Autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting Autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder Cancer cells. Additionally, we detected the participation of the Akt/mTOR signaling cascade in the induction of Autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an Autophagy Inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in Apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved Caspase-3, ki67). These findings demonstrated the cytoprotective role of Autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with Autophagy inhibitors for bladder Cancer treatment.

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