Abstract 1007: Modulation of Claudin 18.2 by chemoradiotherapy in pancreatic and gastric cancer

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Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) and gastric cancer (GCa) are aggressive malignancies with limited response to standard therapies. Claudin 18.2 (CLDN18.2), a tight junction protein aberrantly expressed in these tumors, is a validated therapeutic target. However, its regulation following standard chemotherapy remains unclear, limiting its utility as a stable biomarker in treated patients. This study evaluates the effect of chemotherapy on CLDN18.2 expression in PDAC and GCa to determine its stability and utility as a biomarker in both untreated and post-treatment settings. Methods: CLDN18.2 expression was assessed using both clinical specimens and in vitro models. Chemotherapy-sensitive and -resistant PDAC and GCa cell lines were treated with FOLFIRINOX (PDAC) or FOLFOX (GCa), and surface CLDN18.2 expression was evaluated by flow cytometry at 24 and 96 hours post-treatment. In parallel, CLDN18.2 protein expression was quantified in PDAC tissues using immunofluorescence staining. This cohort included treatment-naïve (n = 7), post-chemoradiotherapy (CRT) responder specimens (n = 9), and matched adjacent non-cancerous pancreas (n = 4). To complement protein-level analysis, bulk RNA sequencing was performed on these tissues. Additionally, an external transcriptomic dataset for 118 human samples was analyzed using RNA-seq data obtained from the Human Tumor Atlas Network (HTAN) database (dbGaP Study Accession: phs002371.v1.p1). The RNA-seq analysis included normal pancreas (n = 4), treatment-naïve PDAC (n = 54), CRT responders (n = 8), partial responders (n = 8), and CRT-resistant tumors (n = 62). Results: Cytotoxicity assay showed significant loss of viability in sensitive PDAC (PANC1, PATU) and GCa (GSU) lines following chemotherapy, whereas resistant lines remained unaffected. CLDN18.2 surface expression was unchanged at 24 hours but significantly upregulated at 96 hours in chemotherapy-sensitive cells in a dose-dependent fashion; resistant cells showed no CLDN18.2 induction. On immunofluorescence staining of human tissues, CLDN18.2 expression was significantly higher in both naïve and post-CRT PDAC tumors compared to normal pancreas, with an overall increase in resected treated tissues, although this change was not statistically significant. Bulk RNA-seq of the same tissues confirmed these findings, and combined analysis of all the tissues with single-cell RNA-seq data showed a trend toward reduced CLDN18.2 in post-CRT responders, whereas treatment-resistant tumors retained CLDN18.2 at levels similar to untreated tumors. Conclusions: CLDN18.2 sustained expression treated PDAC and GCa supports the rationale for integrating CLDN18.2-targeted strategies regardless of prior standard chemoradiotherapy. Further studies are warranted to define optimal timing and predictive value of CLDN18.2 modulation. Citation Format: Yousef Khazaei Monfared, Arvin Haj-Mirzaian, Pedram Heidari, Umar Mahmood, Shadi Abdar Esfahani. Modulation of Claudin 18.2 by chemoradiotherapy in pancreatic and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1007.

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