A member of the type I family of transmembrane glycoproteins possessing tyrosine kinase activity.
A member of the ErbB family of tyrosine kinases which includes ErbB1, ErbB2 (HER-2), ErbB3 and ErbB4 and is encoded by the c-erb protooncogene.
The family of EGF receptors consist of a amino-terminal extracellular domain, a single transmembrane anchor region, and a carboxyl terminal intracellular domain with tyrosine kinase activity.
The activation of its tyrosine kinase receptor leads to auto phosphorylation of the intracellular domain of EGFR.
When there is improper activation of EGFR tyrosine kinase there is increased malignant cell survival, invasion and metastases.
Pathway involves the binding of the EGFR ligand to the receptor causing dimerization and downstream signaling and tyrosine kinase activation which leads to signaling of protein pathways for tumor cell proliferation, metastasis, and increased angiogenesis.
Composed of an extracellular ligand-binding domain, a transmembrane region and an intracellular tyrosine kinase domain.
When ligands bind to the EGFR the intracellular pathway is activated, leading to cell growth, proliferation, and and activation of other signaling pathways.
The extracellular domain binds transforming growth factor alpha and the epidermal growth factor itself.
With extracellular ligand binding the intracellular domain is activated and it triggers cellular mechanism regulating cell growth.
Regulates key pathways involved in cell cycle including mitogen activated protein kinase (MARK) pathway and phosphatidylinositol 3-kinase/AKT pathway.
Receptor dimerization promotes autophosphorylation and triggers down stream signaling via the MARK, PI3K/AKT,and signal transducers and activator of transcription (STAT) pathways.
Mediates increased cell proliferation, reduced apoptosis and increased angiogenesis.
Stimulates proliferation and differentiation of epidermal and epithelial cells.
A mitogen for adult and fetal hepatocytes in culture and its expression enhanced during liver regeneration.
Induces transformation of cells to independent growth.
EGFR signaling pathways influence angiogenesis in the activation and regulation of cellular proliferation.
EGFR up regulation due to kinase activating mutations or increased EGFR expression results in powerful protooncogenic functions causing uncontrolled proliferation and expansion of mutated tumor cells.
It is amplified and mutated in a number of neoplasms.
EGFR mutation driven NSCLC occurs at frequencies of about 10-20% in white patients and 40-60% in Asian patients.
Activating mutations in EGFR are estimated to be present in 15 to 50% of non-squamous advanced non-small cell lung cancers.
Among EGFR mutations 85 to 90% or exon 19 deletions or exon 21 codon substitutions:The current first line therapy for these changes in advanced NSCLC is osimertinib which is a third generation EGFR tyrosine kinase inhibitor.
EGFR gene comprises 28 exons, but activating and sensitizing mutations occur in exons 18 through 21, which encode the site for adenosine triphosphate binding within the tyrosine kinase domain.
Somatic activating mutations in the tyrosine kinase domain of EGFR act as a oncogenic driver leading to ligand -independent activation of receptor downstream Signaling , favoring cell proliferation, survival, and cell migration.
90% of EGFR mutations comprise a lesion within exon 19 or a leucine to arginine substitution mutation in exon 21.
Mutations on exon 19 deletions or point mutations result in a substitution of arginine for leucine at amino acid 858.
Activating EGFR mutations such as exon 19 deletion and exon 21.2 mutation L858R in non-small cell lung cancer cells promotes tumor growth, inhibits aapoptosis, up regulates angiogenic factors, and promotes metastases.
Exon 19 and exon 21 mutations are found in approximately 45% and 40% of patients with EGFR mutations, respectively.
Both mutations are sensitive to EGFR TKIs.
More than 250 EGFR activating and resistance conf2242ing gene mutations have been found.
TKI therapy may be better for exon 19 deletions than exon 21 substitutions.
EGFR mutations are found in approximately 10% of patients with NSCLC, while the incdence in Asia may be as high as 50%.
Mutations in EGFR lead to activate the receptor, resulting in uncontrolled cellular proliferation, tumor growth, and metastases.
Not all mutations lead to EGFR tyrosine kinase activity.
EGFR mutations define a population of patients with non-small cell lung cancer that have the greatest opportunity to experience a response with treatment with a tyrosine kinase inhibitor of EGFR.
It is likely that pure squamous cell carcinomas do not have activating mutations in EGFR, and if such a mutation is present the cancer is either of mixed histology or poorly differentiated adenocarcinoma.
The type of mutation that exists influences the sensitivity to tyrosine kinase inhibitors in lung cancer
The response rate to tyrosine kinase inhibitors are higher in patients whose lung tumors have exon 19 mutations (70-90%) and in patients with exon 21 mutations (20-67%)(Reily GJ, Paz-Ares L).
Patients with exon 20 insertion mutations in EGFR have a worse survival in NSCLC, and a 60% shorter time to treatment failure with an EGFR inhibitor than with platinum based chemotherapy.
Gene mutations frequent in adenocarcinoma of the lung in nonsmokers and are implicated in the development of such lesions.
Increased signaling is crucial for prostate carcinogenesis.
Expressed in normal tissue and in almost all normal epithelial cells, smooth muscle cells and fibroblasts.
Not expressed in hematopoietic cells but overexpressed in head and neck, lung and colorectal cancers, gastric, prostate, esophageal, squamous cell carcinomas, breast, ovarian, cervical glioma, and bladder cancers.
Amplification, mutation and overexpression of various members of the EGFR receptor family have been reported in breast cancer, non-small-cell carcinoma of the lung, colon cancers, glioblastoma, head and neck cancer, medulloblastoma, ependymoma and brainstem glioma.
Overexpressed or upregulated in the majority of colorectal cancers, and a higher degree of staining for EGFR correlates with decreased survival.
Overexpression with squamous cell carcinoma of the head and neck and ovarian cancer correlated with poor prognosis and tumor progression.
Mutations of the EGFR gene have been exclusively found in a subset of pulmonary adenocarcinomas highly sensitive to tyrosine kinase inhibitors for EGFR.
The presence of EGFR mutations an indicator of clinical efficacy of tyrosine kinase inhibitors (TKI) in patients with metastatic or recurrent NSCLC.
EGFR gene mutations correlate with a high probability of response to EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib), and Gilotrif (afatinib).
The two most common EGFR mutations are an exon 19 deletion or an L858R substitution on exon 21, each about 40-45% of the EGFR mutations seen.
The above mutations are associated with long-lasting responses to EGFR TKIs.
In contrast, the other 10-12% of EGFR mutations, most commonly on exon 18 or exon 20, are a heterogeneous group with a less clear benefit from EGFR TKIs.
The exon 19 deletions and exon 21, L858R substitutions represent activating mutations, and have a markedly higher response rate and longer progression-free survival with EGFR TKIs than with standard chemotherapy.
Both mutations are associated with very good responses to TKIs.
EGFR mutations in lung cancer account for 40% of adenocarcinomas of the lung in East Asians and about 15% in Caucasians and African Americans.
EGFR mutations in NSCLC is located primarily in the tyrosine kinase domaine at exons 18 to 21, with exon 19 deletions and exon 21L848R mutations representing the majority of EGFR mutations.
Exon 19 deletions and L858R in EGFR are the most common variants with sensitivity to EGFR-TKIs.
Resistant mutations include T790M and Exon 20 insertions.
Insertions in the gene encoding epidermal growth factor receptor (EGFR) are among the most frequent activating mutations in NSCLC and insertions in exon 20 the third most common type of EGFR mutations, representing up to 12% of all EGFR mutated NSCLCs.
Due to an altered confirmation of the kinase active site limiting the binding of tyrosine kinases inhibitors, NSCLC with insertions in EGFR exon 20 is largely insensitive to tyrosine kinase inhibitors.
The first line, standard therapy for locally advanced or metastatic NSCLC with EGFR exon 20 insertions remains platinum based chemotherapy, with no demonstrated benefit from immunotherapies.
Amivantamab is an EGFR-MET, mesenchymal epithelial transition factor bispecific antibody with immune with immune cell directing activity with multiple mechanisms of action, and when added to chemotherapy results and superior efficacy, as compared with chemotherapy alone, first line treatment of patients with advanced NSCLC with EGFR exon 20 insertions.
Lazertinib is a highly selective CNS penetrate third generation EGFR-TKI with efficacy in both activating the EGFR and T790 M mutations.
Amivantamab-lazertinib is superior in efficacy to osertinib as first line treatment in EGFR mutated advanced NSCLC.
Amivantamab is an EGFR-MET, mesenchymal epithelial transition factor bispecific antibody with immune with immune cell directing activity with multiple mechanisms of action, and when added to chemotherapy results and superior efficacy, as compared with chemotherapy alone, first line treatment of patients with advanced NSCLC with EGFR exon 20 insertions.
Lazertinib is a highly selective CNS penetrate third generation EGFR-TKI with efficacy in both activating the EGFR and T790 M mutations.
Amivantamab-lazertinib is superior in efficacy to osertinib as first line treatment in EGFR mutated advanced NSCLC.