Novel therapeutic strategies targeting the epidermal growth factor. The epidermal growth factor receptor egfr, a member of the erbbher family of receptor proteins, initiates a complex and multilayered signaling cascade which influences many facets of tumor cell. Epidermal growth factor receptor signaling network in pancreatic cancer. Amplification of epidermal growth factor receptor egfr and its active mutant egfrviii occurs frequently in glioblastoma gbm. Pdf targeting the egfr signaling pathway in cancer therapy. Epidermal growth factor receptor signalling in human breast cancer.
The receptor tyrosine kinase signal can be terminated by endocytosis of the phosphorylated receptorligand complex yarden 2001. In 1975, epidermal growth factor egf was found to bind to a cell surface. Epidermal growth factor egf is a protein that stimulates cell growth and differentiation by binding to its receptor, egfr. Sigismund, in progress in molecular biology and translational science, 2016. Egfr signaling pathways that promote the growth and spread of cancer cells. The egfr gene provides instructions for making a receptor protein called the epidermal growth factor receptor, which spans the cell membrane so that one end of the protein remains inside. Seven genetically distinct ligands egf, transforming growth factor. Aberrant epidermal growth factor receptor signaling and. Met signaling overcomes epidermal growth factor receptor. Recent structural studies of epidermal growth factor receptor egfr family extracellular regions have identified an unexpected mechanism for ligandinduced receptor dimerization that has important. Several epidermal growth factor receptor egfr tyrosine kinase inhibitors have been developed and approved by food and drug administration for the treatment of nonsmallcell lung cancers, but their efficacy can be compromised by acquired drug resistance conferred by egfr mutant variants.
They activate a network of signaling pathways that is tightly regulated by. These transmembrane proteins are activated following binding with peptide growth factors of. Epidermal growth factor egf receptor signaling and. Epidermal growth factor receptormediated stat3 signaling. Epidermal growth factor receptor egfr is occasionally amplified andor mutated in nonsmall cell lung cancer nsclc and can be coexpressed with other members of the. A year has passed since mutations of the tyrosine kinase domain of the epidermal growth factor receptor egfr were discovered in patients with nonsmall cell lung cancer nsclc who had. Antiegfr monoclonal antibodies moabs, such as cetuximab or panitumumab, in. Proliferation of mcf7egfr and parental cells was induced by 17. Wildtype egfr is classically activated through ligand binding by factors such as epidermal growth factor egf, transforming growth factor alpha, heparinbinding egflike growth. Epidermal growth factor receptor cell proliferation signaling. Gastric cancers frequently overexpress the epidermal growth factor receptor egfr, which has been implicated in pathological processes including tumor cell motility, invasion and.
Epidermal growth factor receptor egfr signaling in. Epidermal growth factor receptor mutations in lung cancer. It functions in a wide range of cellular processes. Epidermal growth factor receptor egfr and ybox binding protein 1 yb1 are detected in basallike breast cancer specimens on a tumour tissue microarray. The epidermal growth factor receptor egfr is a receptor tyrosine. Epidermal growth factor receptor egfr signaling in cancer. Epidermal growthfactor receptor egfr inhibitors have become a mainstay of treatment of metastatic colorectal cancer mcrc in patients with wildtype ras. The epidermal growth factor receptor egfr belongs to the erbb family of receptor tyrosine kinases rtk. Epidermal growth factor receptor egfr inhibitors are valuable therapeutics in metastatic colorectal cancer mcrc.
The epidermal growth factor receptor egfr is a receptor tyrosine kinase of the erbb family. Epidermal growth factor receptor family activation and. In addition, such egfr mutations increase the susceptibility of patients with nsclc to tyrosine kinase. Epidermal growth factor egf receptors also known as erbb function in development, proliferation and cell survival. Epidermal growth factor receptor egfr phosphorylation. Molecular targeting strategies for cancer therapy are distinct from conventional. Epidermal growth factor receptor egfr is an established therapeutic target in various solid malignancies including squamous cell carcinoma of the head and neck scchn and colon. Structural basis for inhibition of the epidermal growth. Egf receptor signaling has an important role for glycolysis, pentose phosphate pathway, and pyrimidine biosynthesis in egfrmutated lung cancer. Epidermal growth factor receptor egfr is a key factor in epithelial malignancies, and its activity enhances tumor growth, invasion, and metastasis. Growth factor receptor signaling inhibition prevents sars. Telomere length regulation through epidermal growth factor. The phosphorylation of protein kinases leads to the activation of signaltransduction pathways, which have.
Epidermal growth factor receptor cell proliferation. Objectives upregulation of epidermal growth factor receptor egfr is critical for the loss of growth control in a variety of human cancers including squamous cell cancers of the head and neck scchn. Evidence suggests that the egfr is involved in the pathogenesis and progression of different carcinoma types. Assessment and prognostic significance of epidermal growth factor receptor viii mutation in glioblasotma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Evaluation of epidermal growth factor receptor signaling. Egfr binds to its cognate ligand egf, which further. The egfr was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several antiegfr agents available in the clinic. Notch and epidermal growth factor receptor egfr signaling are essential in cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of lung cancer. The epidermal growth factor receptor egfr is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. Epidermal growth factor receptor egfr is expressed in 50% of nsclcs, and its. Egfr epidermal growth factor receptor tocris bioscience. Several epidermal growth factor receptor egfr tyrosine kinase inhibitors have been developed and approved by food and drug administration for the treatment of nonsmallcell lung cancers, but their. The egfr was the first receptor to be proposed as a target.
Therefore, identification of new crosstalk between such pathways may be effective to introduce new strategies for targeted therapy of cancer. Epidermal growth factor receptor as a target in pancreatic. Discovery of potent and selective epidermal growth factor. Epidermal growth factor receptor targeting and challenges. Epidermal growth factor receptors egfrs are a large family of receptor tyrosine kinases tk expressed in several types of cancer, including. Growth factor receptor gfr signaling plays important roles in cancer pathogenesis and has also been reported to be crucial for infection with some viruses beerli et al.
Gfr activation leads to the modulation of a wide range of cellular. The epidermal growth factor receptor egfr is a receptor tyrosine kinase that is commonly upregulated in cancers such as in nonsmallcell lung cancer, metastatic colorectal cancer, glioblastoma, head and. Human egf is 6kda and has 53 amino acid residues and three intramolecular disulfide. Epidermal growth factor receptor inhibition strategies in oncology in. The epidermal growth factor receptor egfr is a long known, versatile signal transducer that has been well conserved during evolution. However, the linkage between oncogenic mutated egfr and cancer cell metabolism has not yet been clearly elucidated. Epidermal growth factor receptor egfr mutations in lung. The epidermal growth factor receptor egfr belongs to a family of receptor tyrosine. Targeting the egfr signaling pathway in cancer therapy ncbi. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in. Epidermal growth factor receptor egfr mutations enable constitutive active downstream signaling of pi3kakt, kraserk and jakstat pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of nonsmall cell lung cancer nsclc.
The egfr was the first receptor to be proposed as a target for cancer therapy, and after 2. Nonsmallcell lung cancer nsclc, the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. Targeted therapeutics that disable signaling molecules upon which in vivo growth and survival advantages of malignant cells pivot, illustrated by gleevec inhibition of bcrabl, are. Advanced nonsmallcell lung cancer nsclc is the leading cause of cancerrelated deaths in the world. The role of epidermal growth factor receptor in cancer metastasis. Epidermal growth factor receptor and notch signaling in. We previously identified plateletactivating factor receptor pafr as being overexpressed in ovarian cancer and found that its ligand paf evoked egfr phosphorylation using the phospho. Decades of research in molecular oncology have brought about promising new therapies which are designed to target specific molecules which promote tumor growth and survival. Mechanisms of acquired resistance to epidermal growth.
The epidermal growth factor receptor egfr is a membrane protein that regulates cell proliferation, differentiation and survival, and is a drug target for cancer therapy. Epidermal growth factor receptor egfr phosphorylation, signaling, and trafficking in prostate cancer 145 2. Egfr, a transmembrane glycoprotein is a member of the erbb receptor tyrosine kinase superfamily. Epidermal growth factor receptor egfr is the key molecular target for nonsmall cell lung cancer nsclc due to its major contribution to complex signaling cascades modulating the survival of. Epidermal growth factor receptor egfr tyrosine kinase inhibitors gefitinib and erlotinib are effective therapies for nonsmall cell lung cancer patients whose tumors harbor somatic. Role of epidermal growth factor receptor in breast cancer. Mutations in the tyrosine kinase epidermal growth factor receptor egfr induce oncogenic addiction in lung adenocarcinoma lad. Epidermal growth factor receptor egfrdependent signaling is involved in many physiological. These transmembrane proteins are activated following binding with peptide growth factors of the egffamily of proteins. Pdf epidermal growth factor receptor egfr signaling in. Research paper assessment of epidermal growth factor.