The Epidermal Growth Factor Receptor (EGFR) is a protein located on the surface of human cells. This receptor plays a role in cellular communication by receiving signals from outside the cell. These signals help regulate fundamental cellular processes, including growth and division.
The Basics of EGFR
EGFR normally functions like an antenna, receiving external signals that instruct the cell to grow and divide. When specific signaling molecules, known as ligands, bind to the external part of EGFR, it triggers a cascade of events inside the cell. This binding causes the receptor to pair with another EGFR protein, a process called dimerization, which activates the receptor complex. This activation then initiates signaling pathways that promote cell proliferation and survival. EGFR is widely expressed in various tissues, including skin and organs, where it supports normal development and wound healing.
How EGFR Mutations Drive Cancer
Alterations, or “mutations,” in the EGFR gene can lead to the receptor being constantly active, even without external signals. This continuous “on” state results in uncontrolled cell growth and division, a hallmark characteristic of cancer. These mutations are typically acquired during a person’s lifetime rather than being inherited. In non-small cell lung cancer (NSCLC), two common activating mutations are deletions in exon 19 and the L858R point mutation in exon 21. Exon 19 deletions, for instance, remove four amino acids from the tyrosine kinase domain, while the L858R mutation involves a single amino acid change, both leading to constitutive activation of the receptor.
Identifying EGFR Mutations
One common diagnostic approach involves analyzing tissue samples obtained through a biopsy. A biopsy involves removing a small piece of the tumor for laboratory analysis to identify specific genetic changes. Another method is a liquid biopsy, which involves analyzing a blood sample for circulating tumor DNA (ctDNA) released by cancer cells. This less invasive approach can also identify EGFR mutations, including those that confer drug resistance. Both methods look for specific genetic alterations like exon 19 deletions or the L858R point mutation.
Targeted Treatments for EGFR-Positive Cancers
Once specific EGFR mutations are identified, doctors employ targeted therapies, primarily EGFR Tyrosine Kinase Inhibitors (TKIs), designed to block the overactive EGFR pathway. These drugs work by fitting into the “on” switch of the mutated EGFR protein, effectively turning it off and hindering cancer cell growth. First-generation TKIs, such as gefitinib and erlotinib, reversibly bind to the ATP-binding pocket of EGFR, inhibiting downstream signaling, while second-generation TKIs, including afatinib and dacomitinib, are irreversible inhibitors that form a covalent bond with EGFR. Third-generation TKIs, like osimertinib, were developed to overcome acquired resistance mutations and are effective against the T790M mutation, while largely sparing wild-type EGFR. These targeted treatments offer a more precise approach compared to traditional chemotherapy, which broadly affects rapidly dividing cells.
Addressing Treatment Resistance
While EGFR TKIs are initially effective, cancer cells can evolve and develop new mutations, leading to treatment resistance. A common resistance mechanism to first and second-generation TKIs is the T790M mutation, occurring in approximately 50-60% of cases. After treatment with third-generation TKIs like osimertinib, a new resistance mutation, C797S, can emerge, often in conjunction with T790M. Strategies to manage resistance include switching to different generations of EGFR TKIs, combining therapies, or exploring clinical trials for novel agents.