Chapter 25 - Overcoming acquired resistance to EGFR-targeted therapy by regulating autophagy

Abstract

Autophagy is a highly conserved metabolic activity that participates in various biological activities, such as biological development and growth. However, autophagy is also a double-edged sword in the process of tumor occurrence and development. It can both promote and inhibit tumor development, which mainly depends on the type of tumor tissue and cells, tumor microenvironment, and tumor stage. Autophagy is mainly divided into two stages: the formation of autophagosomes and the fusion of autophagosomes and lysosomes. The formation of autophagosomes depends on phosphorylated Beclin1 and activated PI3K (VSP34) to form the Beclin1-VPS34 complex. The EGFR-PI3K/AKT/mTOR signaling pathway can inhibit Beclin1 phosphorylation and block autophagy, while the EGFR-PI3K/AKT/mTOR pathway can promote the phosphorylation of Beclin1 and activate autophagy. The relationship between autophagy and EGFR signaling pathways in tumor cells with drug resistance suggests modulation of autophagy for anti-EGFR treatments. In fact, autophagy inhibitors either target autophagosome formation or fusion of autophagosomes and lysosomes work well in some cancers, such as enhancing sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In addition, antigens such as CAGE, which are closely related to autophagy, have been identified as potential targets. Researchers can also combine extracellular vesicles (EVs) and miRNAs to explore candidates for combination therapies that both modulate autophagy and target EGFR.