Epidermal Growth Factor Receptor (EGFR) is a protein found on the surface of various cells throughout the body. It acts as a receiver for external cues, playing a fundamental role in cell signaling. EGFR is involved in regulating cell growth, division, and survival, making it a significant component of normal physiological processes.
Normal Function of EGFR
Under healthy conditions, EGFR functions like a molecular switch that activates upon binding to specific growth factors, known as ligands, such as Epidermal Growth Factor (EGF). When a ligand binds to the external part of EGFR, it causes the receptor to pair up with another nearby EGFR protein, a process called dimerization. This dimerization activates the intracellular portion of the receptor, which possesses tyrosine kinase activity. The activated receptor then sends a cascade of signals inside the cell, promoting essential processes like cell growth, tissue repair, and cell differentiation. This signaling is tightly controlled to ensure balanced cellular activity.
EGFR’s Role in Cancer Development
EGFR can become abnormal in cancer, leading to uncontrolled cell growth and proliferation. One primary mechanism involves specific gene mutations within the EGFR gene, particularly deletions in exon 19 or a point mutation called L858R in exon 21. These activating mutations cause the EGFR protein to be constantly switched on, even without a ligand present. This continuous signaling drives cells to grow and divide excessively, contributing to tumor formation and progression.
Another way EGFR becomes abnormal is through overexpression, where cancer cells produce too many EGFR proteins on their surface. Both mutations and overexpression result in hyperactive EGFR signaling, making cancer cells “addicted” to this pathway. This dysregulation allows cancer cells to evade normal cellular checkpoints, promoting uncontrolled proliferation and hindering programmed cell death.
Targeting EGFR in Cancer Treatment
Understanding EGFR’s role in cancer has led to the development of targeted therapies designed to block these abnormal signals. These therapies are known as EGFR inhibitors, or tyrosine kinase inhibitors (TKIs). TKIs work by interfering with the activated EGFR protein, disrupting the uncontrolled growth signals. This approach is a key part of personalized medicine, where patients are tested for specific EGFR mutations to determine if these drugs will be effective.
The development of EGFR TKIs has progressed through several generations to address drug resistance and improve specificity. First-generation TKIs, such as gefitinib and erlotinib, reversibly bind to EGFR and were effective for patients with sensitizing mutations. However, resistance often emerged due to a secondary mutation called T790M. Second-generation TKIs, including afatinib and dacomitinib, were developed to overcome this resistance by irreversibly binding to EGFR, but they often had dose-limiting toxicities. Third-generation TKIs, like osimertinib, are designed to specifically target the T790M resistance mutation while sparing wild-type EGFR, representing a significant advancement in managing acquired resistance.
Common Cancers Associated with EGFR
EGFR alterations, including mutations and overexpression, are observed in several types of cancer. Non-small cell lung cancer (NSCLC) is the most prominent example, where activating EGFR mutations are found in a significant percentage of patients. These mutations, such as exon 19 deletions and L858R, are strong indicators for response to EGFR TKI therapies.
Beyond NSCLC, EGFR overexpression or mutations can also play a role in other malignancies. These include colorectal cancer, where EGFR is frequently overexpressed, and certain types of head and neck squamous cell carcinoma. Glioblastoma multiforme (GBM) also commonly exhibits EGFR alterations. While EGFR’s relevance varies across these cancers, its presence often guides treatment strategies.