Abstract

Pooled analysis of the SPOTLIGHT and GLOW phase III trials, involving 1072 patients with locally advanced or metastatic gastric/gastroesophageal junction (GC/GEJ) adenocarcinoma positive for claudin18.2 (CLDN18.2) and negative for HER2, showed that zolbetuximab combined with chemotherapy significantly improved progression-free survival (PFS) compared to placebo (HR = 0.72; 95% CI, 0.61–0.84). Subgroup analyses revealed better outcomes in Asian patients, those with gastric cancer, and those with intestinal-type GC. In a cohort of 92 GC patients (immunohistochemical detection based on a CLDN18.2 subtype-specific antibody), CLDN18.2 positivity was associated with lymph node metastasis, advanced cancer stages (III–IV), and shorter overall survival (OS) (HR = 1.728; 95% CI, 1.003–2.977; P  = 0.0404). In our study, knockdown of CLDN18.2 inhibited tumor growth in vivo and in vitro. Additionally, CLDN18.2 knockdown down-regulated minichromosome maintenance (MCM) proteins, particularly MCM2 and MCM5, and decreased phosphorylation of ERK, CDK, and MCM2 in GC cells. These findings provide a theoretical basis for the future selection of advantageous populations for CLDN18.2-targeted therapy and combination therapy strategies.