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Egfr

Official Full Name
epidermal growth factor receptor
Background
The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Mutations in this gene are associated with lung cancer. Multiple alternatively spliced transcript variants that encode different protein isoforms have been found for this gene.
Synonyms
EGFR; epidermal growth factor receptor; epidermal growth factor receptor (avian erythroblastic leukemia viral (v erb b) oncogene homolog) , ERBB; ERBB1; erythroblastic leukemia viral (v erb b) oncogene homolog (avian); proto-oncogene c-ErbB-1; cell growth inhibiting protein 40; cell proliferation-inducing protein 61; receptor tyrosine-protein kinase erbB-1; avian erythroblastic leukemia viral (v-erb-b) oncogene homolog; ERBB; HER1; mENA; PIG61; Errp; ErbB-1; c-erbB; CER; epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase within the ErbB family consisting of 4 members; EGFR (ErbB1, HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). In many different cancer cell types, the ErbB pathway becomes hyperactivated by a series of mechanisms, including overproduction of ligands, overproduction of receptors, or constitutive activation of receptors. Generally, EGFR signaling is triggered by ligand binding to the extracellular ligand binding domain. The typically known ligands are EGF, TGF-alpha, betacellulin, amphiregulin and epiregulin. This initiates receptor homo-/hetero-dimerization and autophosphorylation through the intracellular kinase domain, leading to receptor activation. Following activation, cytoplasmic substrates are phosphorylated and initiate a signaling cascade that drives various cellular responses, including changes in gene expression, apoptosis inhibition, cytoskeletal rearrangement, and increased cell proliferation.

EGFRFigure 1. EGFR and its signal pathway. (Huang L, Fu L. 2015)

The role of EGFR in cancer

Due to its important role in cell survival, proliferation, angiogenesis, and cell differentiation, EGFR-amplification and mutations are key triggers in multiple human cancer cells. Upregulation of the EGFR signaling pathway might result in increased cell growth and proliferation as well as a high potential for the rapid formation of metastases. Overexpression of EGFR, found in bladder, esophageal, cervical, ovarian and head and neck tumors, typically correlates with poor prognosis reflected in the unfavorable progression free survival (PFS) and overall survival (OS) in 70 % of studies. In addition, activating somatic EGFR mutations, especially found in non-small cell lung cancer (NSCLC) patients, nowadays suggest a higher response rate (RR) to tyrosine kinase inhibitors (TKIs) therapies than standard chemotherapy and generally lead to a better prognosis with prolonged PFS compared to patients bearing wild type (WT) EGFR. These activating mutations can act as a predictive factor for prognosis under TKI therapy. This development of dependencies of cancer cells on specific oncogenic signals (like EGFR) may be powerful targets for pharmacotherapy. Finally, this anti-EGF therapy results in tumor cell death induced by BIM, a family member of BCL-2.

EGFR inhibitors and cancer treatment

Targeting the EGFR pathway is a strategy for cancer therapy, including monoclonal antibodies directed against the extracellular domain of the receptor and small molecules inhibiting specific EGFR tyrosine kinases (EGFR-TKIs). Erlotinib and gefitinib are both inhibitors of the tyrosine kinase activity of EGFR and compete with ATP in binding to the tyrosine kinase pocket of the receptor. They have been extensively studied in patients with NSCLC. The presence of somatic mutations in the kinase domain of EGFR, including deletions in exon 19 of the EGFR gene and replacement of leucine with arginine at codon 858, is closely associated with a positive response to gefitinib and erlotinib in NSCLC patients. Despite the benefits of EGFR-TKI in the treatment of NSCLC, most patients finally develop resistance to these drugs. Besides, in other cancers, the efficacy of EGFR-TKIs is low.

Cetuximab, a monoclonal antibody that binds to EGFR, has a higher affinity than the original ligands, prevents receptor activation, inhibits cell proliferation and angiogenesis and promotes antibody-dependent cellular cytotoxicity. Currently, cetuximab is used in combination with either chemotherapy or radiotherapy to treat colorectal and head and neck cancers. However, patients with KRAS mutation may exhibit resistance to cetuximab treatment. Hence, identification of novel strategies or agents to overcome innate and acquired resistance to EGFR-TKIs and cetuximab is an important clinical goal.

Novel strategies that, potentially combined with earlier EGFR-targeting agents, result in enhanced cell killing are therefore still desired. Current research has shown that EGFR-deregulated cells and tumors display alterations in their autophagic response, a pro-survival mechanism that allows cells to recycle nutrients for energy- and macromolecule production. Importantly: (1) EGFR-deregulated cells seem to be more dependent on autophagy for survival and growth; and (2) resistance to EGFR-targeting agents can be reduced by autophagy inhibition, providing a potential novel modality to target these tumors.

References:

  1. Jutten B, Rouschop K. EGFR signaling and autophagy dependence for growth, survival, and therapy resistance. Cell cycle, 2014, 13(1): 42-51.
  2. Juchum M, et al. Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors. Drug Resistance Updates, 2015, 20: 12-28.
  3. Cui J, et al. EGFR inhibitors and autophagy in cancer treatment. Tumor Biology, 2014, 35(12): 11701-11709.
  4. Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharmaceutica Sinica B, 2015, 5(5): 390-401.

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