Giovanni Calice, Carlo Calabrese, Tiziana Notarangelo
Claudins, integral components of tight junctions, have recently emerged as key modulators of drug resistance in gastric cancer. Claudin18.2 is aberrantly expressed in a subset of gastric tumors, where it disrupts epithelial integrity and promotes tumor progression and therapeutic failure. By orchestrating cell death and survival processes, including apoptosis, autophagy, and epithelial-mesenchymal transition pathways, Claudin 18.2 enhances multidrug resistance and is associated with adverse clinical outcomes. Furthermore, its crosstalk with efflux transporters and pro-survival signaling pathways further reinforces chemoresistance to platinum-based drugs and fluoropyrimidines. Growing evidence identifies Claudin18.2 as both a biomarker of aggressive disease and an attractive therapeutic target. Monoclonal antibodies and antibody-drug conjugate directed against Claudin18.2 are currently being evaluated in clinical trials, showing encouraging antitumor activity.