Tumor-Intrinsic PD-1 Regulatory Network Drives Lapatinib Resistance in HER2⁺ Breast Cancer: An Integrative...

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.

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.

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.

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.