Generation of Murine Carcinoma Models with Functional Heterologous HER1 and/or HER2 Receptors for In Vivo Study of Specific Therapies

HER1 and HER2 (human epidermal growth factor receptors 1-2) are essential proteins for cellular physiology. Dysregulation of these receptors plays a key role in tumorigenesis. This turns both oncogenic receptors into targets for antitumor therapies, which currently include passive and active immunotherapy strategies, such as monoclonal antibodies and therapeutic vaccines. In this context, preclinical studies in immunocompetent mice provide insight into these therapies' complex tumor-host interaction and mechanisms of action. However, most therapeutic antibodies and vaccine candidates targeting HER1 and/or HER2 are not cross-reactive for their murine counterparts, which limits the characterization of their effector mechanisms in vivo. Murine models with induced, heterologous expression of human variants of HER1 and HER2 are, hence, needed and scarcely available to date. Herein, we generated and characterized nine tumor models derived from prostate (RM1), lung (Lewis variant 3LL-D122) and breast (4T1) carcinomas expressing HER1 and/or HER2, obtained by lentiviral transduction. Protein expression of the desired antigen and proper folding and insertion in the plasma membrane were confirmed. The functionality of these heterologous targets was demonstrated, in terms of appropriate ligand-induced activation and enhancement of tumor cells proliferation, suggesting that the receptors could engage into the signaling machinery of the modified tumor cells. In addition, incubation of cells from the generated tumor models with specific therapies decreased their viability targeting therapies, indicating the susceptibility of the modified cells to receptors’ inhibition, which advises the utility of the generated models in the characterization of targeted therapies, and their combinations. Overall, generated models are proposed as suitable tools for studying the regulatory roles of HER1 and/or HER2 in the biology of high-incidence carcinomas, as well as to gain deeper insights into the connection of therapies targeting these receptors with the immune system.