Targeting autophagy to enhance Nectin-4-MMAE efficacy in gastric cancer

Nectin-4-MMAE is an innovative antibody-drug conjugate (ADC) that combines a Nectin-4-targeting monoclonal antibody with monomethyl auristatin E (MMAE), a potent microtubule inhibitor, demonstrating substantial therapeutic promise. While previous research has primarily focused on Nectin-4-targeted therapies in urothelial carcinoma, their potential efficacy in gastric cancer (GC) has yet to be thoroughly investigated. To bridge this knowledge gap, this study seeks to investigate the therapeutic effects of Nectin-4-MMAE in GC and examine the mechanistic role of autophagy in the treatment of Nectin-4-positive gastric cancer. Apoptosis and autophagy induced by NECTIN-4-MMAE were validated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, flow cytometry (FCM), transmission electron microscopy (TEM), confocal microscopy, and Western blotting (WB). Gene enrichment analysis was performed based on RNA Sequencing (RNA-seq) data. Finally, the antitumor effects of NECTIN-4-MMAE, with or without the autophagy inhibitor, were confirmed in a mouse xenograft model. Our findings indicate that Nectin-4-MMAE induces both apoptotic cell and protective autophagy. Notably, the combination of Nectin-4-MMAE with autophagy inhibitors demonstrated a markedly stronger inhibitory effect on gastric cancer cells than Nectin-4-MMAE alone. These results suggest a viable therapeutic approach for treating Nectin-4-positive gastric cancer through the combinatorial use of Nectin-4-MMAE with autophagy inhibitors.