Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications

Epidermal growth factor receptor (EGFR) has fundamental roles in normal physiology and cancer, making it a rational target for cancer therapy. Surprisingly, however, inhibitors that target canonical, ligand-stimulated EGFR signaling have proven to be largely ineffective in treating many EGFR-dependent cancers. Recent evidence indicates that both intrinsic and therapy-induced cellular stress triggers robust, noncanonical pathways of ligand-independent EGFR trafficking and signaling, which provides cancer cells with a survival advantage and resistance to therapeutics. Here, we review the mechanistic regulation of noncanonical EGFR trafficking and signaling, and the pathological and therapeutic stresses that activate it. We also discuss the implications of this pathway in clinical treatment of EGFR-overexpressing cancers.

TrendsEGFR is overexpressed and/or hyperactivated in most epithelial cancers, but EGFR-targeting therapies have had limited clinical benefit.Many intrinsic and iatrogenic cellular stresses stimulate ligand-independent EGFR internalization and signaling that provide a survival advantage to tumor cells.Cellular stresses stimulate EGFR internalization and intracellular accumulation with a consequent induction of autophagic responses.Overcoming therapeutic resistance resulting from ligand-independent EGFR functions promises new treatment strategies for EGFR-overexpressing cancers.