Work

MDM2-amplified esophageal adenocarcinomas exhibit an activated metabolic and immunosuppressive phenotype with multiple potential therapeutic targets

Year: 2025

Type: article

Abstract: BACKGROUND: A complete response following neoadjuvant therapy occurs only in a fraction of patients with esophageal adenocarcinoma (EAC). Further targeted treatment options are needed to improve treatment response and patient survival. Mouse double minute 2 homolog (MDM2) is a known oncogene. It is currently under investigation as a potential therapeutic target. However, initial findings have not been groundbreaking. Therefore, this study aimed to identify further potential therapeutic targets in the subtype of MDM2-amplified EAC. METHODS: We screened 656 patients with esophageal adenocarcinoma for their MDM2-amplification status using Fluorescence in situ Hybridization. 57 tumors (8.7%) were MDM2-amplified. The proteome of 35 MDM2-amplified and 37 non-amplified tumors was analyzed using mass spectrometry. RESULTS: The comparison of MDM2-amplified and non-amplified tumors revealed various differently expressed proteins and pathways. Hornerin and Bystin were significantly downregulated. Whereas Choline transporter-like protein 2 and Contactin 1 were upregulated in MDM2-amplified EAC. Enrichment analyses revealed that MDM2-amplified EAC showed a more pronounced immunosuppressive phenotype. Furthermore, distinct metabolic pathways like propanoate and tryptophan metabolism were upregulated. CONCLUSIONS: Summarizing, we described numerous potential therapeutic targets, suggesting patients with MDM2-amplified tumors could potentially benefit from, exemplary, Mitogen-activated protein kinase kinase inhibitors or tryptophan metabolism inhibitors in new combinational treatment regimens. Future mechanistic studies are needed to validate these findings.

Source: BMC Cancer

DOI: 10.1186/s12885-025-15367-3