What is the EGFR Family?
The
epidermal growth factor receptor (EGFR) family is a group of four closely related receptor tyrosine kinases: EGFR (also known as ErbB1 or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). These receptors are involved in the regulation of cell growth, survival, proliferation, and differentiation. They are activated by binding specific ligands, which triggers a cascade of downstream signaling pathways.
How Does the EGFR Family Contribute to Cancer?
The EGFR family plays a prominent role in the development and progression of various cancers. Overexpression or mutation of these receptors can lead to uncontrolled cell division and survival, contributing to
tumorigenesis. For instance, mutations in the EGFR gene are frequently observed in lung adenocarcinomas, while HER2 is commonly amplified in
breast cancer.
Non-small cell lung cancer (NSCLC): Often associated with activating mutations in EGFR.
Breast cancer: Frequently involves overexpression or amplification of HER2.
Colorectal cancer: EGFR overexpression is a common feature.
Head and neck squamous cell carcinomas: Often exhibit EGFR overexpression.
Bladder cancer: EGFR and HER2 alterations have been reported.
Ligand binding: Specific growth factors bind to the extracellular domain of the receptor, causing dimerization and autophosphorylation of the intracellular tyrosine kinase domain.
Gene amplification: Increased copy numbers of EGFR or HER2 genes can lead to overexpression.
Mutations: Point mutations in the gene can result in constitutive activation of the receptor.
Transactivation: Cross-talk with other receptor tyrosine kinases or G-protein-coupled receptors can activate EGFR family members.
RAS-RAF-MEK-ERK pathway: Involved in cell proliferation and survival.
PI3K-AKT pathway: Important for cell survival and growth.
JAK-STAT pathway: Regulates cell proliferation and differentiation.
PLCγ pathway: Linked to cell motility and invasion.
Tyrosine kinase inhibitors (TKIs): Small molecules that inhibit the kinase activity of EGFR family members. Examples include erlotinib, gefitinib, and osimertinib.
Monoclonal antibodies: Target the extracellular domain of the receptor to prevent ligand binding and receptor dimerization. Examples include trastuzumab (HER2) and cetuximab (EGFR).
Antibody-drug conjugates (ADCs): Combine monoclonal antibodies with cytotoxic drugs to deliver targeted therapy. An example is ado-trastuzumab emtansine for HER2-positive breast cancer.
Combination therapies: Combining EGFR inhibitors with other treatments like chemotherapy, radiation, or other targeted therapies to overcome resistance mechanisms.
Resistance: Tumors often develop resistance to EGFR-targeted therapies through secondary mutations, activation of alternative pathways, or phenotypic changes.
Heterogeneity: Tumor heterogeneity can lead to variable responses to therapy.
Toxicity: Targeted therapies can cause significant side effects, limiting their use.
Future research aims to develop more effective treatments by understanding resistance mechanisms, identifying novel targets, and improving patient selection through
biomarkers.
