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Pyrotinib, an irreversible dual EGFR\/HER2 tyrosine kinase inhibitor, has shown clinical efficacy in HER2-driven malignancies, but its potential role in <jats:italic>EGFR<\/jats:italic>-high copy number gastric cancer remains to be investigated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Using <jats:italic>EGFR<\/jats:italic>-high copy number gastric cancer cell lines, primary cells and subcutaneous tumor models in nude mice, we systematically evaluated pyrotinib\u2019s anti-tumor activity through viability assays, apoptosis analysis, and transcriptomic profiling. Mechanistic studies included co-immunoprecipitation, proximity ligation assays, ubiquitination assays, and RNA sequencing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Pyrotinib selectively suppressed proliferation, induced apoptosis, and chemosensitized in <jats:italic>EGFR<\/jats:italic>-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 \u03b3-H2A.X accumulation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>This translational study suggests that pyrotinib combined with oxaliplatin may serve as a promising strategy for patients with <jats:italic>EGFR<\/jats:italic>-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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13046-025-03485-6","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T03:24:07Z","timestamp":1755573847000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pyrotinib targeted EGFR\/GRP78 mediated cell apoptosis in high EGFR gene copy number gastric cancer"],"prefix":"10.1186","volume":"44","author":[{"given":"Lingbo","family":"Bao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyong","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ChunXue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenjie","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuancheng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlu","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"issue":"3","key":"3485_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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