Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer

• Published in: Cell death discovery 2024-09, Vol.10 (1), p.393-11, Article 393
• Main Authors: Xue, Wenjing, Xu, Caili, Zhang, Kaiqi, Cui, Lu, Huang, Xiting, Nan, Yanyang, Ju, Dianwen, Chang, Xusheng, Zhang, Xuyao
• Format: Article
• Language: English
• Subjects: 631/67/1059; 631/67/1504/1829; AKT protein; Antibodies; Antitumor activity; Apoptosis; Autophagy; Biochemistry; Biomedical and Life Sciences; Caspase-9; Cell Biology; Cell Cycle Analysis; Clinical trials; Cytotoxicity; Gastric cancer; Life Sciences; Monoclonal antibodies; Phagosomes; Stem Cells; Therapeutic targets; TOR protein; Tubulin
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-024-02167-0

Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, the inconclusive underlying mechanisms pose a hurdle to extending the utility of these agents. In our study, αCLDN18.2-MMAE, an ADC composed of an anti-CLDN18.2 monoclonal antibody and the tubulin inhibitor MMAE, induced a dose-dependent apoptosis via the cleavage of caspase-9/PARP proteins in CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy was remarkably activated during the αCLDN18.2-MMAE treatment, which was characterized by the accumulation of autophagosomes, the conversion of autophagy marker LC3 from its form I to II, and the complete autophagic flux. Inhibiting autophagy by autophagy inhibitor LY294002 remarkably enhanced αCLDN18.2-MMAE-induced cytotoxicity and caspase-mediated apoptosis, indicating the cytoprotective role of autophagy in CLDN18.2-directed ADC-treated gastric cancer cells. Combination with an autophagy inhibitor significantly potentiated the in vivo antitumoral efficacy of αCLDN18.2-MMAE. Besides, the Akt/mTOR pathway inactivation was demonstrated to be implicated in the autophagy initiation in αCLDN18.2-MMAE-treated gastric cancer cells. In conclusion, our study highlighted a groundbreaking investigation into the mechanism of the CLDN18.2-directed ADC, focusing on the crucial role of autophagy, providing a novel insight to treat gastric cancer by the combination of CLDN18.2-directed ADC and autophagy inhibitor.