The Epidermal Growth Factor Receptor (EGFR) is a protein found on the surface of cells throughout the body. It belongs to a family of proteins called receptor tyrosine kinases, which are involved in cellular signaling. Under normal conditions, EGFR plays a role in controlling cell growth, division, and survival.
When epidermal growth factor (EGF) binds to EGFR, it activates the receptor, initiating internal signals. This signaling pathway instructs the cell to grow, divide, and repair itself. While this process is essential for healthy tissue development and maintenance, an overactive EGFR can lead to uncontrolled cell proliferation, a hallmark of cancer.
Understanding EGFR and Its Oncogenic Role
In healthy cells, EGFR functions as a receptor that binds to growth factors, leading to its activation and subsequent signaling within the cell. This activation typically involves the receptor forming a pair with another EGFR or a related protein, a process called dimerization. This dimerization then triggers a change that allows the receptor to add phosphate groups to itself, which serves as docking sites for other proteins that relay the growth signals further into the cell.
EGFR can transform into an oncogene primarily through mutations in its gene. These mutations lead to the receptor being constantly active, even without the binding of a growth factor. Common mutations include deletions in exon 19 or a specific point mutation known as L858R in exon 21. These alterations lead to continuous activation of downstream signaling pathways, such as the RAS/ERK and PI3K/AKT/mTOR pathways, which are deeply involved in cell proliferation and survival.
The continuous activation driven by these mutations promotes uncontrolled cell proliferation and reduced programmed cell death, known as apoptosis. These specific EGFR mutations are considered “driver mutations” because they directly contribute to the initiation and progression of cancer. They provide a sustained growth advantage to cancer cells, allowing them to multiply without the usual regulatory controls.
Cancers Associated with EGFR Oncogene
The EGFR oncogene plays a significant role in various types of cancer, with non-small cell lung cancer (NSCLC) being the most well-known example. EGFR mutations are found in a substantial subset of NSCLC cases, particularly in adenocarcinomas. These mutations are often seen in patients who have never smoked or are light smokers, and they are more prevalent in certain ethnic populations.
Beyond NSCLC, EGFR mutations or amplification can also be relevant in other cancers. For instance, increased EGFR activity or overexpression has been observed in colorectal cancer. In these cases, the altered EGFR can contribute to tumor growth and progression, though the specific mutations and their responses to therapies may differ from those in NSCLC.
Head and neck squamous cell carcinoma (HNSCC) is another cancer type where EGFR plays a part. While gene mutations might be less common than in NSCLC, overexpression of the EGFR protein is frequently observed. This overexpression can also contribute to the aggressive nature of these tumors, making EGFR an area of interest for therapeutic strategies.
EGFR Targeted Therapies
Targeted therapies for EGFR-driven cancers represent a significant advancement in oncology. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, these therapies are specifically designed to block the overactive EGFR protein. This precision aims to inhibit cancer cell growth while minimizing harm to healthy cells, leading to fewer side effects.
A common class of drugs used for this purpose are Tyrosine Kinase Inhibitors (TKIs). TKIs work by binding to the ATP-binding pocket within the EGFR protein’s active site, preventing the phosphorylation that is necessary for its signaling activity. By blocking this step, TKIs effectively shut down the downstream pathways that drive cancer cell proliferation and survival.
Early TKIs, such as gefitinib and erlotinib, are considered first-generation inhibitors. They effectively block the active site but can face challenges with acquired resistance mutations, like T790M. Second-generation TKIs, including afatinib and dacomitinib, were developed to more potently and irreversibly bind to EGFR, offering improved efficacy and broader coverage of some resistance mutations.
Third-generation TKIs, exemplified by osimertinib, were developed to specifically overcome the T790M resistance mutation, which frequently emerges after treatment with first- or second-generation drugs. These newer TKIs demonstrate increased selectivity for mutated EGFR over wild-type EGFR, leading to better efficacy and a more favorable side effect profile.
Biomarker Testing and Treatment Decisions
Biomarker testing, also known as molecular or genetic testing, plays a role in identifying specific EGFR mutations in cancer patients. This testing is often performed on tumor tissue obtained through a biopsy. Newer methods, such as liquid biopsies, can also detect circulating tumor DNA in blood samples, offering a less invasive option for mutation analysis.
This testing is an important step before initiating treatment for certain cancers, particularly NSCLC. The presence of specific EGFR mutations, such as exon 19 deletions or the L858R point mutation, indicates that a patient is likely to respond well to EGFR-targeted therapies like TKIs. Conversely, the absence of these mutations suggests that targeted therapy would not be effective, guiding clinicians towards alternative treatment approaches.
The results of biomarker testing dictate which targeted therapy is most appropriate for an individual patient. For example, patients with common sensitizing EGFR mutations are often candidates for first-line treatment with EGFR TKIs. If resistance develops during treatment, often due to new mutations like T790M, re-testing can inform subsequent treatment decisions, potentially leading to the use of a different generation of TKI designed to overcome that specific resistance mechanism.