Endocytosis Inhibition for Squamous Cell Carcinoma

Endocytosis Inhibition & Oncology Therapy

Antibody-dependent cell-mediated cytotoxicity (ADCC), in short, is the direct killing of target cells by killing cells (such as NK cells, macrophages, neutrophils,etc.) through their expressed Fc receptors recognizing the Fc segment of the antibody coated on the target antigen. Based on this idea, scientists have developed monoclonal antibodies that recognize different molecular targets, thereby inducing cytotoxic immune effector cells to eliminate virus-infected cells and tumor cells. Some of the more representative monoclonal antibodies include Cetuximab (Anti-EGFR IgG1), Trastuzumab (Anti-HER2 IgG1), and Avelumab (Anti-PD-L1 IgG1). It is worth mentioning here that Avelumab, although it has received general attention by inhibiting the PD1-PDL1 interaction and thereby activating T cell function, can also exert anti-tumor effects by activating ADCC. In fact, although these monoclonal antibodies have achieved certain clinical results, there are still a small number of types of tumors that do not respond to this treatment. In addition, even tumors that respond to this treatment are inclined to resist, leading to tumor recurrence after treatment.

Accumulating evidence suggests that tumor immunotherapy failure may be related to endocytosis. Endocytosis-mediated epidermal growth factor receptor (EGFR) internalization has been shown to be the direct cause of Cetuximab treatment failure, and there is a 100% correlation with the progression of squamous cell carcinoma (SCC).

Methods

This article examines the therapeutic effect of SCC when endocytosis is inhibited with Dyngo4a (an inhibitor of dynamin). In addition, another inhibitor that hinders EGFR internalization, Pistop2 (which can inhibit batch clathrin vesicles (CCVs), was selected to verify whether simply increasing the expression of EGFR on the cell membrane can improve the ADCC response induced by Cetuximab. At the same time, the effect of HER2 endocytosis on the therapeutic effect of Trastuzumab was also investigated. In order to further verify that PCZ can exert its effect on the treatment of tumors in vivo, the previous results were verified in a mouse xenograft model. Finally, considering the efficacy of PCZ in tumor immunotherapy, an exploratory clinical trial was carried out.

Results

Fig.1 Dynogo4a significantly increases the binding of Cetuximab to EGFR on the cell membrane and enhances the tumor-killing effect of monocyte macrophages (PBCMs).¹

Fig.2 Endocytic inhibitors increase ADCC effects in SCC and breast cancer cell lines.¹

Fig.3 Effect of PCZ Therapy in CT26.¹

Fig.4 The effect of PCZ on EGF binding in clinical studies.¹

Conclusion

PCZ, as an inhibitor of endocytosis, has been widely used in clinical practice, such as in the treatment of viral infections, fungal infections, epilepsy, chronic kidney disease, and even for the treatment of cancer. However, the concept of cancer treatment has never been translated into clinical practice, so this paper proves for the first time in vivo that PCZ can indeed inhibit the internalization process of EGFR, which provides strong evidence support for future clinical trials.

Reference

1. Chew, H.Yi; et al. "Endocytosis inhibition in humans to improve responses to ADCC-mediating antibodies." Cell. (2020): 895-914.e27.