Feng Wang, Negar Mottaghi-Dastjerdi, Fatma Altameemi, Behzad Shahbazi, Nahid Ahmadi, Hamed Montazeri, Mohammad Soltany-Rezaee-Rad, Mohammad-Javad Niazi, Fateme Yazdani, Hamed Morad, Nana Li
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.
OBJECTIVES: 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.