CLDN18.2 targeting enhances chemotherapy sensitivity in pancreatic cancer cells and lung cancer organoids.

Claudin 18 isoform 2 (CLDN18.2) is a therapeutic target in solid tumors, but its contribution to chemotherapy response remains unclear. We examined whether CLDN18.2 targeting increases drug sensitivity and whether this is accompanied by changes in solute carrier family 7 member 11 (SLC7A11) expression. High CLDN18 expression was associated with shorter overall survival in pancreatic adenocarcinoma. In DAN-G cells, two independent CLDN18.2 siRNAs increased sensitivity to 5-fluorouracil. TST001 enhanced cisplatin-induced cytotoxicity in lung cancer patient-derived organoids. CLDN18.2 knockdown also reduced SLC7A11 mRNA, increased sensitivity to Ras-selective lethal 3 (RSL3), and increased RSL3-induced membrane lipid peroxidation. TST001 and IMAB362 reduced SLC7A11 mRNA, and TST001 increased RSL3 sensitivity in KATO III and NUGC4 cells. Confocal images were consistent with IMAB362 internalization and partial lysosomal localization. These findings support CLDN18.2 targeting as an approach to chemotherapy sensitization in the models tested. Reduced SLC7A11 expression and altered lipid-peroxidation responses are possible contributors, but their causal involvement in chemotherapy sensitization remains to be established.