EGFR targeting for cancer therapy: Pharmacology and immunoconjugates with drugs and nanoparticles.

Abstract The epidermal growth factor receptor (EGFR) belongs to the tyrosine kinase receptors family and is present in the epithelial cell membrane. Its endogenous activation occurs through the binding of different endogenous ligands, including the epidermal growth factor (EGF), leading to signaling cascades able to maintain normal cellular functions. Although involved in the development and maintenance of tissues in normal conditions, when EGFR is overexpressed, it stimulates the growth and progression of tumors, resulting in angiogenesis, invasion and metastasis, through some main cascades such as Ras/Raf/MAPK, PIK-3/AKT, PLC-PKC and STAT. Besides, considering the limitations of conventional chemotherapy that result in high toxicity and low tumor specificity, EGFR is currently considered an important target. As a result, several monoclonal antibodies are currently approved for use in cancer treatment, such as cetuximab (CTX), panitumumab, nimotuzumab, necitumumab and others are in clinical trials. Aiming to combine the chemotherapeutic agent toxicity and specific targeting to EGFR overexpressing tumor tissues, two main strategies will be discussed in this review: antibody-drug conjugates (ADCs) and antibody-nanoparticle conjugates (ANCs). Briefly, ADCs consist of antibodies covalently linked through a spacer to the cytotoxic drug. Upon administration, binding to EGFR and endocytosis, ADCs suffer chemical and enzymatic reactions leading to the release and accumulation of the drug. Instead, ANCs consist of nanotechnology-based formulations, such as lipid, polymeric and inorganic nanoparticles able to protect the drug against inactivation, allowing controlled release and also passive accumulation in tumor tissues by the enhanced permeability and retention effect (EPR). Furthermore, ANCs undergo active targeting through EGFR receptor-mediated endocytosis, leading to the formation of lysosomes and drug release into the cytosol. Herein, we will present and discuss some important aspects regarding EGFR structure, its role on internal signaling pathways and downregulation aspects. Then, considering that EGFR is a potential therapeutic target for cancer therapy, the monoclonal antibodies able to target this receptor will be presented and discussed. Finally, ADCs and ANCs state of the art will be reviewed and recent studies and clinical progresses will be highlighted. To the best of our knowledge, this is the first review paper to address specifically the EGFR target and its application on ADCs and ANCs.