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The epidermal growth factor receptor (EGFR) is commonly considered the “prototypical” receptor tyrosine kinase (RTK). It is one of the family of four RTKs in humans, the others being ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 (Figure 1). EGFR and its relatives are known oncogenic drivers in cancers such as lung cancer, breast cancer, and glioblastoma, and inhibitors of these receptors have been among the most successful examples of targeted cancer therapies to date, including antibody therapeutics and small-molecule tyrosine kinase inhibitors.
ErbB receptors and their ligands
EGFR is regulated by at least seven different activating ligands in humans (Figure 1): EGF itself, transforming growth factor a (TGF-α), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (ARG), epiregulin (EPR), and epigen (EGN). Each contains an EGF-like domain which is responsible for receptor binding and activation, with a characteristic pattern of six spatially conserved cysteines. The EGFR ligands are all produced as membrane-bound precursor proteins and are cleaved by cell-surface proteases to yield the active growth factor species. Although defects in EGFR affect a broad range of processes, it still remains unclear which ligands are responsible in which context—with a few exceptions. ErbB3 and ErbB4 are regulated by neuregulins (NRGs) —also called heregulins (HRGs), a family of ligands produced from four genes (NRG1-NRG4) in a wide variety of isoforms which all contain an EGF-like domain. NRG1 and NRG2 bind both ErbB3 and ErbB4, but NRG3 and NRG4 appear to be ErbB4 specific. The NRGs and their receptors play an important role in nervous system development. NRG1 and ErbB4 have also been linked to schizophrenia. And three of the EGFR ligands mentioned above (BTC, EPR, and HB-EGF) can bind and activate ErbB4 and are termed “bispecific” ligands.
Figure 1. Schematic representation of EGFR/ErbB family receptors and their ligands.
Nuclear accumulation of ErbB family members and transactivation of signaling
EGFR family members initiate signaling from the cell membrane and the signal is transmitted to the nucleus through cytoplasmic intermediates. Several tyrosine kinase receptors like the VEGF receptor, NGF receptor and FGF receptor or their fragments have been known to enter the nucleus from the plasma membrane by diverse mechanisms and may act as a kinase or a transcription factor in the nucleus. EGFR and its family members such as HER2, rat p185neu, HER3 and truncated C-terminal HER4 have been consistently detected in the nucleus of tumor specimens of many organs such as breast, oral cavity, ovary, esophagus, cervix, skin and prostate with poor clinical prognosis. Several lines of evidence suggest that receptor internalization is the initial step for nuclear translocation and involves interaction with nuclear import proteins such as importin beta1 for HER2 and importin beta1 and importin alpha1 for EGFR.
Recent reports have pointed out that EGFR receptors lack a putative DNA-binding domain, therefore it is presumed that following nuclear entry these EGFR receptors will interact with DNA-binding transcription factors. In addition, reports also indicate the RNA helicase A is a DNA-binding partner of EGFR and regulates the transcription of its target genes in the nucleus of cancer cells. To this end, frequent overexpression of inducible nitric oxide synthase, cyclin D1 and B-Myb are connected with the promoter-binding ability of the nuclear accumulated EGFR with STAT3 and E2F1 cofactors (Figure 2).
Figure 2. The nuclear accumulation and receptor internalization of EGFR family members
Given the functional involvement of EGFR in diverse cellular processes, several approaches have been developed that target and interfere with EGFR-mediated effects. Two distinct therapeutic approaches currently employed for targeting EGFR in many human malignancies are the use of monoclonal antibodies and small-molecule tyrosine kinase inhibitors (TKIs). Each of these approaches has a distinct mechanism of action; while anti-EGFR antibodies bind to extracellular domains, TKIs target the intracellular TK domains. Recent studies have indicated the use of various chemopreventive agents in downregulating EGFR at the gene level. Furthermore, several studies substantiated and conferred significant benefits of anti-EGFR agents in several types of solid tumors including head, colorectal and neck cancer, non-small cell lung cancer (NSCLC) and pancreatic cancer in terms of overall survival, progression-free survival and overall response rate.
The monoclonal antibodies against EGFR are specifically designed to be directed against the extracellular region of EGFR that creates a ligand competitive inhibition, thus preventing receptor dimerization, auto-phosphorylation and downstream signaling. Apart from inhibiting EGFR signaling, these monoclonal antibodies will induce receptor internalization, ubiquitination, degradation and prolonged downregulation.
TKIs are small molecules that are either reversible or irreversible by nature. They exist as adenosine triphosphate (ATP) analogs and inhibit EGFR signaling by competing and binding with ATP-binding pockets on the intracellular catalytic kinase domain of RTKs, thereby preventing autophosphorylation and activation of several downstream signaling pathways.
Exploring the EGFR family members and their corresponding signaling pathways have provided us with an unfathomable knowledge in understanding the molecular basis of epithelial malignancies. This has enabled us to develop EGFR-targeted therapies, some of which have been approved for human use. Since EGFR plays an integral role in malignant cell growth, proliferation, motility and survival of cancer cells and is widely observed in several malignancies, it is one of the first molecules to be selected for the treatment of cancer. Although this signaling cascade has been studied for many years, several aspects still remain elusive to us. For example, it is unclear how the gene copy number, mutational status and EGFR overexpression impact various intracellular signaling pathways in cancer. This remains as a major obstacle because of the crosstalk between EGFR family members and other signaling pathways, leading to therapeutic resistance. Research has to be focused on other directions, such as identifying a biomarker that can predict anti-EGFR therapy response.