Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Identification of key genes and pathways involved in trastuzumab resistance in HER2‑positive gastric cancer through integrative bioinformatics analysis

Articles in Press

Document Type : Original Article

Authors
Feng Wang 1, 2
Negar Mottaghi-Dastjerdi 3
Fatma Altameemi 3
Behzad Shahbazi 4, 5
Nahid Ahmadi 4
Hamed Montazeri 3
Mohammad Soltany-Rezaee-Rad 6
Mohammad-Javad Niazi 7
Fateme Yazdani 3
Hamed Morad 8
Nana Li 9
1 Henan Key Laboratory of Medical Tissue Regeneration, Henan Medical University, Xinxiang, Henan 453003, China
2 Central Laboratory, Peking University Shenzhen Hospital, Shenzhen 518036, P.R. China
3 Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
4 School of Pharmacy, Semnan University of Medical Sciences, Semnan, Iran
5 Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
6 Behestan Innovation Factory, Behestan Darou, Tehran, Iran
7 Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
8 Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
9 Henan Key Laboratory of Medical Tissue Regeneration, School of Basic Medical Sciences, Henan Medical University, Xinxiang, Henan 453003, China
10.22038/ijbms.2026.95195.20528
Abstract
Objective(s): Trastuzumab resistance limits therapeutic efficacy in HER2-positive gastric cancer, and its systems-level regulatory architecture remains poorly characterized. This study aimed to identify key regulatory modules, biomarkers, and candidate therapeutic targets associated with trastuzumab resistance.
Materials and Methods: Gene expression profiles from trastuzumab-sensitive and -resistant gastric cancer cell lines (GSE77346) were analyzed to identify differentially expressed genes (DEGs). Protein–protein interaction (PPI) networks were constructed, and hub genes were identified using topology-based methods and clustering. Functional enrichment analysis was performed using Gene Ontology and KEGG pathways. Prognostic relevance was evaluated using TCGA-STAD data via UALCAN. Drug–gene interactions were explored using DrugBank and PHAROS, followed by structural modeling and molecular docking.
Results: Trastuzumab resistance was linked to transcription factor-driven reprogramming, cytoskeletal and adhesion remodeling, and receptor tyrosine kinase (RTK) bypass signaling. Eleven hub genes were identified across four functional modules potentially associated with FGFR signaling, epithelial–mesenchymal transition (EMT), and lineage plasticity. Elevated PXDN and CDH2 expression was significantly associated with poor overall survival in TCGA-STAD. Molecular docking provided preliminary in silico evidence for potential interactions between selected compounds, including ADH-1, AGX51, artenimol, and phenethyl isothiocyanate, and candidate targets, including N-cadherin/CDH2, ID3, and vimentin.
Conclusion: Trastuzumab resistance may involve networks related to transcriptional plasticity, adhesion dynamics, and RTK redundancy. This study provides a hypothesis-generating framework for future biomarker-guided combination strategies, which requires validation in HER2-positive cohorts and experimental models.
Keywords
Bioinformatics
Biomarkers
Drug resistance
Gastric cancer
Gene expression profiling HER2
Protein interaction maps
Trastuzumab
Subjects
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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 31 August 2026