A novel and promising therapeutic approach for treating pancreatic cancer: Nectin‑4‑targeted antibody‑drug conjugates alone or combined with autophagy inhibitors

Fu,Rong; Wang,Chunbin; Yin,Tongjin; Zhang,Xuyao; Xu,Ying; Shi,Yue; Xu,Jing; Zhang,Wei; Ding,Zhe

doi:10.3892/ijmm.2025.5507

A novel and promising therapeutic approach for treating pancreatic cancer: Nectin‑4‑targeted antibody‑drug conjugates alone or combined with autophagy inhibitors

Authors:
- Rong Fu
- Chunbin Wang
- Tongjin Yin
- Xuyao Zhang
- Ying Xu
- Yue Shi
- Jing Xu
- Wei Zhang
- Zhe Ding
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Affiliations: Department of Pharmacy, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng, Jiangsu 224008, P.R. China, Department of Oncology, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng, Jiangsu 224008, P.R. China, Department of Pediatrics, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng, Jiangsu 224008, P.R. China, Department of Biological Medicines and Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, Shanghai 201203, P.R. China, Department of Pharmacy, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng, Jiangsu 224008, P.R. China
Published online on: February 24, 2025 https://doi.org/10.3892/ijmm.2025.5507
Article Number: 66
Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Antibody‑drug conjugates (ADCs) are rapidly advancing the treatment of solid tumors, and Nectin‑4‑targeted ADCs have been approved by the FDA to treat certain cancers. Although Nectin‑4 is overexpressed in the tissues of patients with pancreatic cancer, whether Nectin‑4‑targeted ADCs can effectively treat pancreatic cancer remains unclear. The present study evaluated the therapeutic effects and mechanisms of Nectin‑4‑targeted ADCs in pancreatic cancer. A Nectin‑4‑directed ADC was chosen, Nectin‑4‑MMAE, which triggered apoptosis and induced cell death in the Nectin‑4‑positive pancreatic cancer cell lines BxPC‑3 and YAPC. Nectin‑4‑MMAE also induced autophagy in BxPC‑3 and YAPC cells by inactivating the AKT/mTOR pathway. The entire autophagy process was observed by electron microscopy and laser confocal microscopy. The autophagy inhibitors LY294002 and chloroquine significantly increased the lethal effects of Nectin‑4‑MMAE on BxPC‑3 and YAPC cells by inducing apoptosis. In the xenograft tumor model, Nectin‑4‑MMAE alone elicited potent antitumor effects. When Nectin‑4‑MMAE was combined with autophagy inhibitors, the tumor burden of mice was decreased compared with treatment with either drug alone. The present study confirmed the potent therapeutic effects of Nectin‑4‑MMAE against pancreatic cancer, and its unique antitumor mechanism provides new approaches to treatment.

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