ArticleGastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association2025
Identification of CD66c as a potential target in gastroesophageal junction cancer for antibody-drug conjugate development.
Article in Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Immuno-cytotoxic convergence: integrating antibody‒drug conjugates and immunofusion proteins to overcome resistance in gastrointestinal cancers.Journal of hematology & oncology · 2026Review
- Integrative Omics Analysis Reveals the Potential Value of CEACAM6 in Pan-Gastrointestinal Cancers.Immunity, inflammation and disease · 2026Article
- Antibody-drug conjugates in cancer therapy: current landscape, challenges, and future directions.Molecular cancer · 2025Review
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Authors and funding
10 authors.
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Abstract
backgroundGastroesophageal junction (GEJ) cancer exhibits unique biological characteristics and currently lacks specific targeted therapies. Given the clinical efficacy of antibody-drug conjugates (ADCs) in solid tumor treatment, we aimed to identify a novel ADC target and suitable payload for GEJ-targeted therapy.
methodsIn this study, we conducted bioinformatic analyses of multi-omics data, including transcriptomics, proteomics, and phosphoproteomics, to identify CD66c as a promising ADC target for GEJ cancer. We then engineered a CD66c-directed antibody-drug conjugate (CD66c-DXd) incorporating a GGFG linker. The preclinical efficacy of CD66c-DXd was determined in multi GEJ xenograft models.
resultsProteomic analyses of 103 cases of GEJ cancer revealed that CD66c expression was significantly higher in tumoral tissues compared to normal tissues. Proteomic and phosphoproteomic analyses identified deruxtecan (DXd) as a potentially potent payload for ADCs targeting GEJ cancer. Furthermore, high CD66c expression in GEJ was associated with a significantly lower proportion of plasma cells. The drug-to-antibody ratio (DAR) of CD66c-DXd was determined to be 3.6. CD66c-DXd effectively and selectively ablated multiple human GEJ cell lines (OE-19, OE33 and SK-GT-4) without affecting non-malignant cells (GES-1) in vitro. Eventually, CD66c-DXd mediated potent and durable tumor regression in vivo with excellent safety profiles.
conclusionsThis preclinical study provides a strong rationale for the further development of CD66c-DXd as promising therapeutic candidates to treat advanced GEJ cancer. Additionally, the study demonstrates the robustness of the multi-omics data in identifying novel potential ADC targets and payloads.
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