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Background <p>COP9 Signalosome Subunit 5 (COPS5) is a deubiquitinating enzyme that induces chemotherapy resistance. The role of <i>COPS5</i> amplification in patients with gastric cancer (GC) and its therapeutic potential in <i>HER2</i>-amplified GC models have not been explored.</p> Methods <p>The Cancer Genome Atlas (TCGA) data were analyzed to assess the clinical relevance of <i>COPS5</i> amplification in patients with GC. Functional studies using <i>HER2</i>-amplified GC cell lines and xenograft models evaluated the effects of COPS5 inhibition (CSN5i-3), alone or in combination with trastuzumab.</p> Results <p>In the curated stomach adenocarcinoma cohort (n = 294) from TCGA datasets, <i>COPS5</i> amplification was significantly more frequent in patients with <i>HER2</i> amplification (10.5% vs. 2.7%, P = 0.040) and was associated with worse disease-free survival after surgery (median 12.6 vs. 45.2&#xa0;months, P = 0.012) and overall survival (median 21.4&#xa0;months vs. not reached, P = 0.004). In <i>HER2</i>-amplified GC cell lines, CSN5i-3 treatment synergized with the antiproliferative effect of trastuzumab. Mechanistically, <i>COPS5</i> knockout enhanced PTEN expression by ubiquitin-mediated SNAIL degradation, suppressing the AKT downstream pathway. The combination effect was dependent on PTEN expression. Accordingly, <i>COPS5</i> knockout enhanced the efficacy of AKT inhibitors. In a xenograft model, the combination of CSN5i-3 and trastuzumab demonstrated synergistic antitumor effects compared to monotherapy.</p> Conclusions <p><i>COPS5</i> amplification was significantly more prevalent in patients with <i>HER2</i> amplification and was associated with poor outcomes after surgery. The synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the inhibition of the AKT pathway, warranting further clinical studies in patients with HER2-positive GC.</p>

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COPS5 inhibition synergizes with the antitumor effect of trastuzumab by PTEN upregulation in HER2-amplified gastric cancer

  • 期刊论文

  • 发表日期：

    2025年10月2日

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  • Sung-Hyun Hwang,
  • Ji-Won Kim,
  • Haeseong Park,
  • Andrew J. Aguirre,
  • Kui-Jin Kim,
  • Songji Choi,
  • Woochan Park,
  • Jeongmin Seo,
  • Heejung Chae,
  • Minsu Kang,
  • Eun Hee Jung,
  • Koung Jin Suh,
  • Se Hyun Kim,
  • Jin Won Kim,
  • Yu Jung Kim,
  • Jee Hyun Kim,
  • Keun-Wook Lee

摘要

Background

COP9 Signalosome Subunit 5 (COPS5) is a deubiquitinating enzyme that induces chemotherapy resistance. The role of COPS5 amplification in patients with gastric cancer (GC) and its therapeutic potential in HER2-amplified GC models have not been explored.

Methods

The Cancer Genome Atlas (TCGA) data were analyzed to assess the clinical relevance of COPS5 amplification in patients with GC. Functional studies using HER2-amplified GC cell lines and xenograft models evaluated the effects of COPS5 inhibition (CSN5i-3), alone or in combination with trastuzumab.

Results

In the curated stomach adenocarcinoma cohort (n = 294) from TCGA datasets, COPS5 amplification was significantly more frequent in patients with HER2 amplification (10.5% vs. 2.7%, P = 0.040) and was associated with worse disease-free survival after surgery (median 12.6 vs. 45.2 months, P = 0.012) and overall survival (median 21.4 months vs. not reached, P = 0.004). In HER2-amplified GC cell lines, CSN5i-3 treatment synergized with the antiproliferative effect of trastuzumab. Mechanistically, COPS5 knockout enhanced PTEN expression by ubiquitin-mediated SNAIL degradation, suppressing the AKT downstream pathway. The combination effect was dependent on PTEN expression. Accordingly, COPS5 knockout enhanced the efficacy of AKT inhibitors. In a xenograft model, the combination of CSN5i-3 and trastuzumab demonstrated synergistic antitumor effects compared to monotherapy.

Conclusions

COPS5 amplification was significantly more prevalent in patients with HER2 amplification and was associated with poor outcomes after surgery. The synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the inhibition of the AKT pathway, warranting further clinical studies in patients with HER2-positive GC.