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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Karl Knipper,
  • Christiane J. Bruns,
  • Felix C. Popp,
  • Thomas Schmidt,
  • Bastian Grothey,
  • Alexander Quaas,
  • Su Ir Lyu

摘要

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.