Figure 1.

Schematic showing the intracellular trafficking and pharmacological inhibitors of EGFR. (A) Shows the internalization and degradation of EGFR, seen in normal polarized epithelium; EGFR is first internalized through clathrin-mediated endocytosis, then undergoes trafficking through the endosomal network before being degraded in the lysosome; (B) the retrograde trafficking of EGFR is depicted, beginning with clathrin-mediated endocytosis; EGFR is then bound by sorting nexins (SNXs) and the retromer within the endosome, inducing further retrograde trafficking to the nucleus; within the nucleus EGFR drives oncogenic pathways through several mechanisms; (a) an EGFR targeted monoclonal antibody is depicted binding EGFR at the cell surface, inhibiting ligand binding and subsequent activation; (b) an EGFR specific TKI is depicted inhibiting EGFR signal transduction from the plasma membrane and the endosome in both normal cells and tumor cells; (c) the EGFR retrograde trafficking inhibitor cSNX1.3 is shown blocking the interaction of EGFR and cSNX1.3 which blocks the nuclear accumulation of EGFR. AKT: protein kinase B; cSNX1.3: capped sorting nexin peptide 1.3; ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinase; ESCRT: endosomal sorting complex required for transport; JAK: Janus kinase; MEK: mitogen-activated protein kinase kinase; mTOR: mechanistic target of rapamycin; MVB: multivesicular body; PDK1: 3-phosphoinositide-dependent kinase 1; PI3K: phosphatidylinositol 3-kinase; RAF: rapidly accelerated fibrosarcoma; RAS: rat sarcoma virus; Sec61: transmembrane translocon channel; STAT: signal transducer of activators of transcription