2. Academic Validation
  3. COPS5 inhibition synergizes with the antitumor effect of trastuzumab by PTEN upregulation in HER2-amplified gastric cancer

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

  • Gastric Cancer. 2025 Oct 2. doi: 10.1007/s10120-025-01669-9.
Sung-Hyun Hwang 1,  Ji-Won Kim 2 3,  Haeseong Park 4,  Andrew J Aguirre 4,  Kui-Jin Kim 1,  Songji Choi 5 6,  Woochan Park 5,  Jeongmin Seo 5,  Heejung Chae 5,  Minsu Kang 5,  Eun Hee Jung 5,  Koung Jin Suh 5,  Se Hyun Kim 5,  Jin Won Kim 5,  Yu Jung Kim 5,  Jee Hyun Kim 5 6,  Keun-Wook Lee 5
Affiliations

Affiliations

  • 1 Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea.
  • 2 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 13620, Republic of Korea. jiwonkim@snubh.org.
  • 3 Department of Genomic Medicine, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea. jiwonkim@snubh.org.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 5 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 13620, Republic of Korea.
  • 6 Department of Genomic Medicine, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea.
PMID: 41039054 DOI: 10.1007/s10120-025-01669-9
Abstract

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.

Keywords

COPS5; Gastric cancer; PTEN; SNAIL; Trastuzumab.

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