Association Between CLDN18 and MUC1 Could Drive Novel Targeted Therapy Options in GI Cancers

With the use of gene expression profiling, there is evidence of an association between Claudin 18 (CLDN18) and MUC1 genes in gastrointestinal cancers, according to Aditya Shreenivas, MD, MS.1

At the 2025 Gastrointestinal Cancers Symposium, Shreenivas and colleagues presented on the use of gene expression profiling to evaluate the association between CLDN18 and MUC1 in gastrointestinal cancers.

“There are CAR T-based therapies and targeted therapies that are targeting MUC1, so [I wonder if] there is a role for finding an association between [CLDN18 and MUC1],” Shreenivas said during an interview with OncLive®. “Secondly, could there be a role for targeting both of these biomarkers at the same time? That was the main reason why we went after this specific association.”

In October 2024, the FDA approved zolbetuximab-clzb (Vyloy), a CLDN18.2-directed cytolytic antibody, along with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2-positive, confirmed by an FDA-approved test.2

However, although there are established associations between CLDN18 and MUC1, there isn’t a treatment available that can target both biomarkers, which warrants future studies to evaluate the role of CLDN18-based therapies, Shreenivas noted.

In the interview, Shreenivas discussed the rationale for evaluating the association between MUC1 and CLDN18 in gastrointestinal cancers, findings from the analysis, and current challenges regarding CLDN18 testing and therapies to target both biomarkers.

Shreenivas is an assistant professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California.

OncLive: What was the rationale for evaluating the use of gene expression profiling to examine the association between MUC1 and CLDN18 in gastrointestinal cancers?

Shreenivas: This is part of a larger project to evaluate whether CLDN18 has an interaction with other biomarkers in gastrointestinal cancers. CLDN18 is a tight junction protein, and it's present in normal cells; however, when there is malignant transformation, cells lose their polarity, and all of these biomarkers, especially CLDN18, due to the change in position, become more accessible to a novel therapeutic approach.

We've seen the FDA approval of zolbetuximab, which is an IgG1 monoclonal antibody that targets CLDN18.2. There are several other antibody-drug conjugates [ADCs], high-affinity antibodies, and CAR T-cell [therapies] that have been utilized to target CLDN18. Similarly, MUC1 is also [expressed] on epithelial cells and is a marker for more aggressive cancer, again, with multiple malignant transformations. Its polarity also changes, making it more susceptible and a possible target for therapies.

[For this research], I am collaborating with a company called Datar Cancer Genetics based out of India and Europe. This was based on a sample size of 1000 patients—a heterogeneous population. Most of the data come from Asia, so it's nice to have a heterogeneous population from Southern Asia and Europe to analyze the prevalence of these biomarkers. 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.

What were the key findings from this analysis?

We did some initial analysis to see if there was any statistical significance relationship between PD-L1, TMB, and HER2, but we didn't find anything at this level. Later on, more studies will probably show some associations. Overall, we know that there is a lot of tumor heterogeneity that we have to deal with in CLDN18, just like HER2 and PD-L1. In the future, we would have to come up with therapeutic modalities that either work with a lower expression for CLDN18, or come up with modalities that have bispecific antibodies, for example, that target multiple pathways at the same time. Perhaps MUC1 may be one of those additional biomarkers that could work in conjunction with CLDN18, and we could develop therapeutic strategies to target both of them.

We also reviewed multiple other genomic alterations seen in different tumor types that were CLDN18 expressing, and we did extensive analysis of that. Having a better understanding of the molecular heterogeneity of different tumors expressing CLDN18 would be helpful going forward. There are some real-world implications in the future for CLDN18. Therefore, [having] a better understanding of expressions in metastatic sites vs the primary tumor and having a better understanding of the interplay between HER2, PD-L1, and TMB, would also be very helpful in the future.

With CLDN18 testing, what has already been established, what are some current challenges, and what is your perspective on this so far?

For example [with other targeted therapies], when we had approval for a RET inhibitor or NTRK inhibitors, we were already doing next-generation sequencing [NGS] profiling. We had those reports, so we could find those patients and offer them therapy. With CLDN18, we have a companion test now. Once this was approved, most institutions, including academic institutions, were not prepared for the companion test. Since this CLDN18 inhibitor, zolbetuximab, based on [data from the phase 3] SPOTLIGHT [NCT03504397] and GLOW [NCT03653507] trials, is only approved in the first-line setting, it's a time-sensitive issue to offer therapies to patients. When most patients come to the clinic, we are not ready to offer them zolbetuximab because we don't have the testing available.

Also, it's a problem of plenty: should we use immunotherapy in combination with chemotherapy? Should we use a CLDN18 inhibitor along with chemotherapy? What about those patients who are HER2-positive? There are issues in terms of sequencing.

The third issue is tumor heterogeneity. When we go ahead and biopsy a metastatic site, chances are that the CLDN18 expression would be much lower. Zolbetuximab is [currently] approved at a higher threshold. Unless patients have a 75% or greater CLDN18 expression, they would not qualify for that therapy. That also is an important point we need to consider. However, future studies with combination biomarkers will help us decide which therapeutic strategy is better over the other. If you look at [the phase 3] CheckMate 649 trial [NCT02872116] and SPOTLIGHT data, the hazard ratio of survival was much better in CheckMate 649 for patients who had a PD-L1 combined positive score [CPS] of greater than 10. In clinical practice right now, if a patient comes in with a PD-L1 CPS score of 10, I offer them immunotherapy first, instead of offering them zolbetuximab. There's no head-to-head trial to warrant use of one of the strategies over the other. The other main question that we could delve into in the future is, can we take up a chemotherapy-free approach for all of these patients who have triple-positive or double-positive tumors, as we sometimes have utilized in other tumors?

A lot of questions still need to be answered. We need consensus building. We need SOPs at different institutions so that we reduce the turnaround time for testing, and we have SOPs in place in terms of sequencing therapies as well.

References

1. Shreenivas AV, Gaya AM, Shaikh M, et al. Use of gene expression profiling to examine the association between MUC1 and claudin 18 in gastrointestinal cancers: implications for targeted therapies. J Clin Oncol. 43(suppl 4):838. doi: 10.1200/JCO.2025.43.4_suppl.8
2. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed March 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma