Dr Shreenivas on the Association Between MUC1 and CLDN18 in GI Cancers

"We did extensive gene expression profiling, looking at the upregulation and downregulation of pathways, and we found a very strong correlation between MUC1 and CLDN18.”

Aditya Shreenivas, MD, MS, assistant professor, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses findings from a gene expression profiling analysis of the association between Claudin 18 (CLDN18) and MUC1 in gastrointestinal (GI) cancers, and their potential implications for targeted therapy development.

In this multi-institutional study, Shreenivas and colleagues conducted genomic profiling on samplesfrom heterogeneous patient populations across Southern Asia and Europe. These included 651 upper and lower GI cancer samples, 316 pancreaticobiliary cancer samples, and 76 hepatocellular carcinoma samples.

The study assessed the expression patterns of CLDN18, a tight junction protein, and MUC1, an epithelial biomarker associated with aggressive malignancies. The analysis aimed to determine whether co-expression of these biomarkers could inform novel therapeutic strategies. Potential correlations between CLDN18 expression and established molecular markers, including PD-L1, tumor mutational burden, and HER2, were also evaluated.

Findings presented at the 2025 ASCO Gastrointestinal Cancers Symposium demonstrated that Claudin 18 was upregulated in 20% of analyzed samples (n = 321). Among cases with concurrent MUC1 and CLDN18 gene expression data (n = 118), MUC1 overexpression was observed in all CLDN18–positive tumors. However, no statistically significant correlation was identified between CLDN18 and HER2, PD-L1, TMB, or microsatellite instability (MSI), suggesting that CLDN18 may serve as an independent predictive biomarker. Additional genomic analyses revealed frequent gene amplifications in MYC (13%), ERBB2 (5%), and CCND1 (5%). MSI-high cases accounted for 2.4% of the overall cohort.

Shreenivas notes that the spatial reorganization of these biomarkers during malignant transformation may enhance their accessibility to therapeutic agents. CLDN18 has emerged as a viable therapeutic target, as demonstrated by the approval of zolbetuximab, a monoclonal antibody directed against CLDN18. Additionally, other investigational therapies, including antibody-drug conjugates, high-affinity antibodies, and CAR T-cell therapies, are being explored for CLDN18–positive tumors.

Shreenivas highlights the strong correlation between MUC1 and CLDN18 expression, suggesting the potential for dual-targeting approaches in future therapeutic strategies. He emphasizes the need for further validation through immunohistochemical assays and the development of bispecific antibodies capable of targeting both pathways simultaneously. Additionally, future studies will investigate tumor heterogeneity and optimize treatment modalities that account for varying levels of CLDN18 expression.

Shreenivas concludes that these findings underscore the potential role of MUC1 and CLDN18 as complementary biomarkers in GI cancers, highlighting the need for continued research to refine personalized treatment strategies incorporating targeted therapies.