Targeting the EGFR signaling pathway in cancer therapy

Abstract

Introduction: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts.

Areas covered: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also presented in this review.

Expert opinion: EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, a further understanding of the system is required to develop an effective anticancer regimen. A combination therapy that comprises an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy.

Figure 1a. Structural elucidation of EGFR

EGFR family members share a common domain arrangement comprised of a cysteine-rich extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain with several phosphorylation sites. The extracellular domains are subdivided and numbered as I-IV. Numerous phosphorylation sites were mentioned in cytoplasmic domain of EGFR. Monoclonal antibodies target the extracellular domain III. The small molecule tyrosine kinase inhibitors bind with the ATP binding pockets in the tyrosine kinase domain. Several deletion mutations occur in the EGFR such as EGFRvI (AA^Δ1–541), EGFRvIII (AA^Δ6–273), EGFRvII (AA^Δ521–603), EGFRvIV (AA^Δ959–1053) and EGFRvV (AA^Δ959–1186). Additionally, several point mutations occur in TK domain of EGFR. Furthermore, the details of EGFR mutations were discussed by Kuan et al.2001 [116]. (AA^Δ amino acid deletion).

Figure 1b. Structures of all four human EGF receptors' extracellular regions with their respective ligands

EGFR can specifically bind with EGF, TGF-α, AR, BTC and EPR ligands. HER2 is an orphan receptor with no known ligand. HER3 lacks intrinsic tyrosine kinase domain and binds to Herregulin-1, 2 (HRG-1&2). HER4 binds to HRG1-4, NRG1-4, HB-EGF, BTC and EPR.

Figure 2. The nuclear accumulation and receptor internalization of EGFR family members

Upon signal activation, EGFR accumulates in the nucleus facilitated by binding with transcription factors E2F1 and STAT3 through importins, leading to up-regulation of B-Myb, iNOS and Cyclin D1. HER2 interacts with importin 2 and is internalized, leading to the expression of Cox-2, PRPK, MMP-16 and PDX-10. HER4 interacts with STAT5a and the C-terminal fragment alone accumulates in the nucleus after undergoing gama secreatase mediated cleavage.

Figure 3. Schematic representation of EGFR inhibition in multidimensional approaches

(1) Therapeutic invention site for EGFR specific monoclonal antibodies (Cetuximab and Panitumumab), (2) Potential target for small molecule tyrosine kinase inhibitors (Gifitinib, Erlotinib, Lapatinib and Canertinib), (3) Synergistic role of chemopreventive agents (Genistein, Curcumin and Caspacin).