The lysosome as a novel therapeutic target of EGFR-mediated tumor inflammation

Abstract

EGFR-mediated tumors have been targeted to overcome several different malignant cancers. EGFR overexpression and mutations are directly related to the malignancy, which makes the therapy more complicated. One reason for the malignancy is the induction of AP1 followed by inflammation via IL-6 secretion. Current therapeutic strategies to overcome EGFR-mediated tumors are tyrosine kinase inhibitors (TKIs), anti-EGFR monoclonal antibodies, and the combination of these two agents with classic chemotherapy or immune checkpoint inhibitors (ICIs). Although the strategies are straightforward and have shown promising efficacy in several studies, there are still hurdles to overcoming the adverse effects and limited efficacy. This study reviews the current therapeutic strategies to target EGFR family members, how they work, and their effects and limitations. We also suggest developing novel strategies to target EGFR-mediated tumors in a novel approach. A lysosome is the main custodial staff to discard unwanted amounts of EGFR and other receptor tyrosine kinase molecules. Targeting this organelle may be a new approach to overcoming EGFR-mediated cancers.

Keywords: EGFR; ErbB; TKI; combination therapy; lysosome.

FIGURE 1

The lysosome activation drives the degradation of EGFR. The binding of EGF initiates the endocytosis of EGFR, inducing downstream signals. The endocytosed EGFR in endosomes is being recycled in tumor cells with EGFR mutation or overexpression (A). However, the activation of lysosomes gives the drive force to the lysosomal degradation of endocytosed EGFR rather than the recycling (B). Created with Biorender.com.

FIGURE 2

EGFR activation and downstream signaling cascade. EGFR activation induces not only MAPK/PI3K pathways, but also NF-κB and STAT pathways for cell survival and inflammation.