Tumor-Intrinsic PD-1 Regulatory Network Drives Lapatinib Resistance in HER2⁺ Breast Cancer: An Integrative Bioinformatics Analysis
Year: 2026
Type: article
Abstract: BACKGROUND: Lapatinib resistance evolution in HER2+ breast cancer is still a crucial therapeutic hurdle, with immune microenvironmental reprogramming playing a minimally explored role. Beyond its canonical expression on T cells, programmed cell death protein 1 (PD-1/PDCD1) is intrinsically induced in resistant breast tumors. Through the binding of tumor-intrinsic PD-1 to PD-L1 on adjacent tumor or stromal cells, inhibitory signals are generated, establishing an immunosuppressive microenvironment. METHODS: This exploratory study investigated the tumor-intrinsic (PD-1)-lapatinib resistance (PLR) regulatory network driving lapatinib resistance in HER2⁺/ER-/PR- breast cancer using an integrative bioinformatics analysis. The GSE38376 dataset and PDCD1 co-expressed genes were utilized to construct the protein-protein interaction (PPI) of the PLR regulatory network. Gene expression patters were visualized using a complex heatmap. Gene ontology, KEGG functional enrichment, gene-metabolite interaction network, immune cell infiltration, comparative gene expression profiling, correlation analysis of PDCD1-hub genes, survival analysis, and genetic alterations analysis were performed on the PLR regulatory network to elucidate the mechanisms of lapatinib resistance. RESULTS: Pathways and gene-metabolite analyses showed that the PLR regulatory network genes were enriched in immune regulation pathways and lipid metabolic reprogramming. The top 10 PLR-hub genes were identified. Expression profiling in lapatinib-resistant cells revealed the upregulation of PDCD1, B2M, and ITGB2, while other genes, particularly those involved in interferon response and antigen presentation, were downregulated. Immune infiltration analysis indicated exhausted T cells and an immunosuppressive microenvironment. Comparative gene expression and survival analyses of PLR-hub genes implicated the PLR regulatory network in lapatinib resistance. Genetic alterations were infrequent, suggesting that regulation may occur epigenetically or transcriptionally. CONCLUSION: The findings revealed that the PLR regulatory network is associated with HER2⁺/ER-/PR- lapatinib resistance through multiple mechanisms, including interferon signaling silencing, T cell exhaustion, and the fostering of an immunosuppressive niche. These insights pave the way for interventions aimed at overcoming lapatinib resistance in HER2⁺ breast cancer.
Authors: Ahmed Alhallaq, Nadeen Sultan
Institution: Al-Azhar University – Gaza
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $200
OpenAlex ID: W7128354138
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