The Epidermal Growth Factor Receptor, or EGFR, is a protein found on the surface of many cells throughout the body. Its normal function involves receiving signals from external growth factors, triggering processes inside the cell. These signals regulate cellular activities like growth, division, and survival, ensuring proper tissue and organ development and maintenance.
When a growth factor binds to EGFR, it causes the receptor to connect with another nearby EGFR protein, activating a complex that initiates signaling pathways within the cell. This controlled activation is important for healthy cell function. However, changes in the EGFR protein can disrupt this balance, leading to uncontrolled cell proliferation and potentially contributing to cancer development.
Understanding EGFR and Its Role in Cancer
When the EGFR protein becomes abnormal due to mutations or overexpression, it can send continuous “grow” signals, even without external growth factors. This unregulated signaling leads to uncontrolled cell proliferation, a hallmark of cancer development.
In some cancers, EGFR acts as a “driver,” meaning its abnormality is a primary cause of the cancer’s growth and spread. For instance, mutations in the EGFR gene are commonly associated with non-small cell lung cancer (NSCLC), particularly adenocarcinoma. These mutations can make the EGFR protein constitutively active, bypassing normal regulatory mechanisms and driving tumor progression.
Normal EGFR activation involves growth factors binding to initiate signaling pathways, including Ras/MAPK and PI3K/AKT, which regulate cell growth, differentiation, and survival. In cancer, this finely tuned system is disrupted. Abnormal EGFR can also impact tumor suppressor gene function, enhancing cell proliferation and genomic instability. The most frequent EGFR mutations in lung cancer involve deletions in exon 19 or a point mutation in exon 21 (L858R). These mutations account for approximately 90% of all EGFR mutations in NSCLC. Other, less common mutations include insertions in exon 20 and point mutations in exon 18.
Identifying EGFR Status in Cancer
Determining EGFR abnormalities in a patient’s cancer is a routine part of diagnosis. This testing predicts how well a patient might respond to certain targeted therapies, guiding treatment decisions.
Tissue samples obtained from a tumor biopsy are a common method for testing EGFR status. Pathologists use molecular tests like next-generation sequencing (NGS) or polymerase chain reaction (PCR) to identify specific genetic mutations within the EGFR gene.
An alternative, less invasive method is a liquid biopsy, which involves a blood test. This test looks for fragments of tumor DNA, known as circulating tumor DNA (ctDNA), that have entered the bloodstream. Liquid biopsies can be useful when a tissue biopsy is difficult to obtain or when monitoring treatment response over time. While liquid biopsies have high specificity, tissue biopsy remains important, especially if blood test results are negative, due to potentially lower sensitivity.
Targeted Therapies for EGFR-Driven Cancers
Targeted therapies block the abnormal EGFR pathway in cancer cells. These drugs interrupt continuous growth signals from mutated EGFR, inhibiting cancer cell growth and promoting cell death. Tyrosine kinase inhibitors (TKIs) are the main type of targeted therapy used for EGFR-driven cancers.
EGFR TKIs bind to the ATP-binding site of the EGFR’s tyrosine kinase domain, preventing phosphorylation of downstream signaling molecules. This action stops the activation of pathways that would otherwise promote cell growth and survival. By selectively targeting the mutated EGFR, these drugs aim to minimize harm to healthy cells.
First-generation EGFR TKIs, such as gefitinib and erlotinib, showed improvements in progression-free survival compared to traditional chemotherapy for patients with specific EGFR mutations. Second-generation EGFR TKIs, including afatinib and dacomitinib, followed. These drugs often bind irreversibly to the EGFR kinase domain and can inhibit other related receptors like HER2, offering broader inhibition.
Third-generation EGFR TKIs, such as osimertinib, are further advancements. These drugs are more specific to certain EGFR mutations, including those causing resistance to earlier generations, and often have improved ability to penetrate the blood-brain barrier. Common side effects across these generations of TKIs can include skin reactions like acne-like rash, dry skin, and nail changes, as well as gastrointestinal issues such as diarrhea and mouth sores, and sometimes elevated liver enzymes.
Addressing Treatment Resistance
While EGFR-targeted therapies are effective initially, cancer cells can develop resistance, causing treatment to become less effective over time. This acquired resistance is a challenge in managing EGFR-mutant cancers. Most patients experience progression after a median of 10 to 16 months of treatment with first-generation TKIs.
One common mechanism of acquired resistance is the emergence of new mutations within the EGFR gene, particularly the T790M mutation in exon 20. This mutation accounts for approximately 50% of resistance cases, preventing the TKI drug from binding effectively to the EGFR protein and leading to renewed tumor growth. Other resistance mechanisms include activation of alternative signaling pathways that bypass the inhibited EGFR, or changes in the cancer cell type.
Strategies to overcome resistance involve switching to newer generations of EGFR inhibitors. For instance, third-generation TKIs like osimertinib were specifically developed to target the T790M resistance mutation. These newer drugs can effectively inhibit the resistant EGFR. Combination therapies, such as combining an EGFR TKI with chemotherapy or other targeted agents, are being explored to delay or overcome resistance by targeting multiple pathways or mechanisms simultaneously.