The Epidermal Growth Factor Receptor (EGFR) is a protein on the surface of cells that helps regulate their growth and division. Sometimes, the gene that produces this protein undergoes a change called amplification, where a cell creates too many copies of the EGFR gene. This alteration is significant in cancer because the resulting excess of EGFR protein can disrupt normal controls on cell behavior, leading to uncontrolled growth.
What is EGFR and Gene Amplification?
The EGFR protein is a receptor on the cell’s outer membrane that acts as a switch for cellular growth. This switch is turned on when a growth factor molecule binds to it, signaling the cell to grow and divide as part of normal tissue maintenance and repair.
A gene provides the instructions for building a protein. Gene amplification is a process where the cell makes numerous extra copies of a specific gene. With EGFR amplification, the cell has far more than the usual two copies of the EGFR gene, leading to the overproduction of its corresponding protein.
The surface of the affected cell becomes crowded with an abnormally high number of EGFR receptors. The number of receptors can increase from a normal range of 40,000–100,000 per cell to over 1 million in some cancer cells. This density of receptors makes the cell highly sensitive to growth signals.
Connection to Cancer Development
The excess of EGFR proteins on a cell’s surface is directly linked to cancer development. With so many receptors, the cell becomes hyper-responsive to growth signals, receiving constant instructions to divide even without high levels of growth factors. This disrupts the normal cell cycle and leads to uncontrolled proliferation, a hallmark of cancer.
This continuous signaling drives cells to multiply, which can result in tumor formation. EGFR amplification is a known feature in several cancers, most prominently glioblastoma (an aggressive brain cancer) and certain non-small cell lung cancers. Its presence is often associated with more aggressive disease and a poorer prognosis.
This alteration is also found in other malignancies, including colorectal, head and neck, and some breast cancers. In these cases, the excess EGFR receptors contribute to tumor progression by sending sustained signals for the cell to grow and divide.
Diagnostic Testing for EGFR Amplification
Diagnosing EGFR amplification requires a biopsy, where a tissue sample is removed from the tumor for analysis. Technicians use specialized tests to check for extra copies of the EGFR gene or an overproduction of the EGFR protein.
Fluorescence In Situ Hybridization (FISH)
This technique uses fluorescent probes that attach to the EGFR gene within a cell’s DNA. Under a microscope, these glowing probes allow scientists to count the EGFR gene copies in each cell. A high number of fluorescent signals per cell indicates that amplification has occurred.
Immunohistochemistry (IHC)
This test measures the amount of EGFR protein on the surface of cancer cells. IHC uses antibodies that bind to the EGFR protein and produce a colored stain. The intensity of this stain reveals the protein level, with a strong stain suggesting a high concentration resulting from gene amplification.
Next-Generation Sequencing (NGS)
NGS is a technology that analyzes a large portion of a tumor’s DNA at once. It can detect EGFR amplification along with a wide range of other genetic mutations. This provides a more complete genetic profile of the tumor to help guide treatment decisions.
Targeted Therapies for Treatment
The discovery of EGFR amplification led to the development of targeted therapies. Unlike traditional chemotherapy, these drugs are designed to specifically attack cancer cells with this vulnerability. The goal is to block the overactive signaling from the excess EGFR proteins.
Tyrosine Kinase Inhibitors (TKIs)
One class of EGFR inhibitors is tyrosine kinase inhibitors (TKIs). These small molecules enter the cell and attach to the internal part of the EGFR protein. This action blocks the receptor’s “on” switch, preventing it from signaling the cell to divide.
Monoclonal Antibodies
Another class of inhibitors is monoclonal antibodies. These larger molecules work outside the cell by binding to the external portion of the EGFR protein. This physically blocks growth factors from attaching, which prevents the receptor from being activated and can also flag the cancer cell for destruction by the immune system.
While targeted therapies can be effective, tumors may develop new mutations that allow growth signaling to continue despite the drug, a phenomenon called treatment resistance. Ongoing research focuses on developing newer generations of EGFR inhibitors to combat these resistance mechanisms.