Functional HER1/HER2-Expressing Murine Tumor Models for Preclinical Evaluation of Targeted Therapies

Background: HER1 and HER2 are critical receptors involved in tumorigenesis and the development of targeted therapies for various carcinomas. However, most antibodies and drugs currently in development do not recognize murine orthologs, which restricts their evaluation in immunocompetent models. Methods: We generated nine tumor models through the lentiviral transduction of murine prostate (RM1), lung (3LL-D122), and breast (4T1) carcinoma cell lines, subsequently validating them in immunocompetent BALB/c and C57BL/6 hosts. Receptor expression and functionality were characterized using flow cytometry, immunoblotting, proliferation assays, and therapeutic sensitivity testing. Results: Transduced cells exhibited stable membrane expression of HER1/HER2 and ligand-induced phosphorylation, confirming receptor functionality. In all three tumor models generated, the expression of HER1 and/or HER2 significantly enhanced cell proliferation compared to parental lines. Furthermore, treatment with specific monoclonal antibodies and the tyrosine kinase inhibitor markedly reduced the viability of cells expressing HER1 and/or HER2, without affecting negative controls. Conclusions: These models provide a robust and reproducible platform for the preclinical evaluation of HER1/HER2-targeted therapies in immunocompetent hosts. Although the current model relies on subcutaneous implantation and does not fully replicate the native tumor microenvironment, it represents a crucial first step toward the development of orthotopic and immunologically relevant models for translational cancer research.