Chemotherapy-induced cell cycle arrest is associated with increased claudin-18 isoform 2 expression and enhanced zolbetuximab-mediated cytotoxicity in gastric cancer.

Abstract

Background: Claudin-18 isoform 2 (CLDN18.2) is a tight junction protein expressed in gastric mucosa and gastric cancer (GC) cells. Although chemotherapeutic agents are suggested to increase CLDN18.2 expression in GC cells, their impact on GC tissues and their underlying mechanisms remain unclear.

Methods: We examined the effects of chemotherapy on CLDN18.2 expression in human GC tissues and cell lines, and investigated the role of cell-cycle regulation in this process.

Results: We found that CLDN18.2 expression was upregulated in GC tissues after chemotherapy. In GC cell lines (SNU-601, NUGC4, GSU), chemotherapeutic agents, including 5-fluorouracil, irinotecan, paclitaxel, and cisplatin, increased CLDN18.2 expression at the transcriptional level, although the response patterns varied among cell lines and agents. Since cell-cycle regulation appeared to be involved, we tested cyclin-dependent kinase (CDK) inhibitors and found that CDK1- and CDK4/6-specific inhibitors similarly enhanced CLDN18.2 expression. Importantly, both chemotherapeutic agents and CDK inhibitors significantly increased zolbetuximab-mediated antibody-dependent cellular cytotoxicity in GC cells.

Conclusion: These results suggest that chemotherapeutic agents upregulate CLDN18.2 in GC cells at least in part through cell cycle arrest, and support combining zolbetuximab with chemotherapy and/or CDK inhibitors for GC treatment.