2. Academic Validation
  3. Pyrotinib targeted EGFR/GRP78 mediated cell apoptosis in high EGFR gene copy number gastric cancer

Pyrotinib targeted EGFR/GRP78 mediated cell apoptosis in high EGFR gene copy number gastric cancer

  • J Exp Clin Cancer Res. 2025 Aug 19;44(1):245. doi: 10.1186/s13046-025-03485-6.
Lingbo Bao # 1 2,  Xudong Wang # 1,  Xiuyong Liao # 3,  Dong Li # 2,  ChunXue Li # 4,  Nan Dai 1,  Xiaoyan Dai 1,  Jing Yang 1,  Nana Hu 1,  Xueling Tong 1,  Zhenjie He 1,  Yuancheng Zhao 5,  Zheng Liu 1 2,  Yue Hu 1,  Jinlu Shan 6,  Dong Wang 7,  Mengxia Li 8,  Qian Chen 9
Affiliations

Affiliations

  • 1 Cancer Center of Daping Hospital, Army Medical University, Chongqing, 400037, China.
  • 2 Department of Oncology, General Hospital of Western Theater Command, Chengdu, 610083, China.
  • 3 Department of Oncology, Chongqing University Qianjiang Hospital, Qianjiang Central Hospital of Chongqing, No. 360, South Section of Zhengzhou Road, Qianjiang District, Chongqing, 409000, China.
  • 4 Department of General Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China.
  • 5 Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu, 610083, China.
  • 6 Cancer Center of Daping Hospital, Army Medical University, Chongqing, 400037, China. lulu7476@tmmu.edu.com.
  • 7 Department of Oncology, Chongqing University Qianjiang Hospital, Qianjiang Central Hospital of Chongqing, No. 360, South Section of Zhengzhou Road, Qianjiang District, Chongqing, 409000, China. Wangdong64@hotmail.com.
  • 8 Cancer Center of Daping Hospital, Army Medical University, Chongqing, 400037, China. limengxia@tmmu.edu.cn.
  • 9 Cancer Center of Daping Hospital, Army Medical University, Chongqing, 400037, China. 13chenqian@tmmu.edu.cn.
  • # Contributed equally.
PMID: 40830980 DOI: 10.1186/s13046-025-03485-6
Abstract

Background: Despite frequent Epidermal Growth Factor Receptor (EGFR) amplification and overexpression in gastric Cancer, limited therapeutic responses were observed in existing EGFR-targeted agents. Pyrotinib, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor, has shown clinical efficacy in HER2-driven malignancies, but its potential role in EGFR-high copy number gastric Cancer remains to be investigated.

Methods: Using EGFR-high copy number gastric Cancer cell lines, primary cells and subcutaneous tumor models in nude mice, we systematically evaluated pyrotinib's anti-tumor activity through viability assays, Apoptosis analysis, and transcriptomic profiling. Mechanistic studies included co-immunoprecipitation, proximity ligation assays, ubiquitination assays, and RNA Sequencing.

Results: Pyrotinib selectively suppressed proliferation, induced Apoptosis, and chemosensitized in EGFR-high copy number gastric Cancer models. Mechanistically, pyrotinib promoted EGFR-GRP78 (Glucose-regulated protein 78) complex formation in the endoplasmic reticulum, activating the protein kinase R-like endoplasmic reticulum kinase/ activating transcription factor 4/ C-EBP homologous protein (PERK/ATF4/CHOP) axis to drive ER stress-mediated Apoptosis. Concurrently, pyrotinib inhibited GRP78 phosphorylation at Thr62, triggering K48-linked ubiquitination (ubiquitin chains formed via lysine 48 linkages) and proteasomal degradation, which impaired DNA double-strand break (DSB) repair and sensitized cells to oxaliplatin-induced γ-H2A.X accumulation.

Conclusion: This translational study suggests that pyrotinib combined with oxaliplatin may serve as a promising strategy for patients with EGFR-high copy number gastric Cancer and highlighted the discovery of this previously unknown EGFR/ GRP78 signaling axis, which provides the molecular basis and the rationale to target EGFR.

Keywords

EGFR; GRP78; Pyrotinib; TRIM21; Ubiquitination.

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