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

Sep 23, 2026

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Antibody-drug conjugates (ADCs) are advancing solid-tumor therapy, and Nectin-4-targeted ADCs have been approved for certain cancers. Although Nectin-4 is highly expressed in pancreatic cancer tissues, its therapeutic value for this disease is not fully defined. This study assessed Nectin-4-directed ADC (Nectin-4-MMAE) in Nectin-4-positive pancreatic cancer models, showing apoptosis induction and autophagy activation via AKT/mTOR pathway inactivation. Autophagy inhibition with LY294002 or chloroquine enhanced cytotoxicity, and in vivo xenografts demonstrated strong anti-tumor effects with reduced tumor burden when combination therapy was applied.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

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Abstract

Introduction

Background on pancreatic cancer and current treatments

Rationale for targeted ADC therapy

Nectin-4 as an antigen target

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 55: 66, 2025 A novel and promising therapeutic approach for treating pancreatic cancer: Nectin‑4‑targeted antibody‑drug conjugates alone or combined with autophagy inhibitors RONG FU 1* , CHUNBIN WANG2* , TONGJIN YIN3* , XUYAO ZHANG4 , YING XU 1 , YUE SHI 1 , JING XU 1 , WEI ZHANG 1 and ZHE DING 1 1 Department of Pharmacy, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, 2 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; 3Department of Pediatrics, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, Yancheng, Jiangsu 224008, P.R. China; 4Department of Biological Medicines and Shanghai Engineering Research Center of Immunotherapeutic, Fudan University School of Pharmacy, Shanghai 201203, P.R. China Received October 30, 2024; Accepted February 5, 2025 DOI: 10.3892/ijmm.2025.5507 Abstract . Antibody‑ drug conjugates (AD Cs) 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 micros‑ copy. The autophagy inhibitors LY294002 and chloroquine significantly increased the lethal effects of Nectin‑4‑MMAEon BxPC‑3 and YAPC cells by inducing apoptosis . In thexenograft tumor model, Nectin‑4‑MMAE alone elicited potent antitumor effects . When Nectin‑4‑MMAE was combined with autophagy inhibitors, the tumor burden Correspondence to: Mr. Wei Zhang or Mr. Zhe Ding, Department of Pharmacy, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital, 2 Xindu West Road, Yandu, Yancheng, Jiangsu 224008, P.R. China E‑mail: [zwjudas@163.com](zwjudas@163.com) E‑mail: [ycsyyxb@126.com](ycsyyxb@126.com) *Contributed equally Key words: Nectin‑4‑MMAE, antibody‑drug conjugate, pancreatic cancer, autophagy, apoptosis, combination therapy 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. Introduction Pancreatic cancer is a highly lethal cancer, accounting for nearly 5% of cancer‑related deaths worldwide (1) . Numerous patients with pancreatic cancer are diagnosed in the late stages of the disease because there are no apparent symptoms, resulting in missed opportunities for surgical treatment . The main treatments for pancreatic cancer are pancreatectomy and drug chemotherapy, but the prognosis for patients is poor. Despite advances in combination chemotherapy, the median survival of patients with pancre‑ atic cancer is only 10‑12 months (2,3) . Due to the limited efficacy of current treatment options, targeted therapies are receiving attention for addressing this unmet clinical need (4) . Of significant note, antibody‑drug conjugates (ADCs) have become a popular research topic in antitumor drug development, combining the advantages of precise targeting and efficient elimination to achieve exact and effi‑ cient elimination of cancer cells . Since the U. S. FDA first approved the ADC d

FAQs

What is the main therapeutic strategy studied in this paper?

The study evaluates Nectin-4-targeted antibody-drug conjugates using Nectin-4-MMAE, tested alone or combined with autophagy inhibitors.

How does Nectin-4-MMAE affect pancreatic cancer cells?

Nectin-4-MMAE triggers apoptosis and induces cell death in Nectin-4-positive pancreatic cancer cell lines. It also induces autophagy by inactivating the AKT/mTOR pathway.

What is the role of autophagy inhibitors in the treatment regimen?

Autophagy inhibitors such as LY294002 and chloroquine significantly increase the lethal effects of Nectin-4-MMAE by enhancing apoptosis. In xenograft models, combination therapy decreases tumor burden compared with either drug alone.

Sep 23, 2026

Uploaded by Ezra