The topic of what is EGFR is one that really deserves to have been covered here from the beginning, but somehow I skipped to the drugs and what they do in cancer patients. It’s time to take a step back and discuss EGFR and why it’s been an important target in cancer.
EGFR stands for Epidermal Growth Factor Receptor, and it can be targeted from the outside of the cell by intravenous monoclonal antibodies against the target protein (also known as a ligand) binding portion of the cell, or from the inside of the cell by oral small molecule inhibitors against the part of the receptor called the tyrosine kinase domain that activates the intracellular machinery:
(click to enlarge)
EGFR is actually just one of a family of four receptors, called human epithelial receptors, or the HER family, that each are activated by different ligands or in some cases no known ligand. EGFR is another name for HER1, and HER2 is a receptor that is very important in many patients with breast cancer.
These receptors are activated by one of their activating ligands and pair up with another receptor in the HER family, either one of the same receptors (homodimerization) or a different one (heterodimerization). This process leads to the activation of the back end of the receptors and a cascade of activities inside of the cell.
These activities are quite complex, but the overall effect is to increase activation of many genes and facilitate cell cycle progression, so overall this promotes cell growth and division. Overall, this leads to many activities that are good for the cell but bad for the person if it’s a cancer cell, because it increases the cell’s likelihood of survival, turns of self-regulating cellular self-destruct programming (called apoptosis), facilites the cell’s ability to invade other tissues and metastasize, and even increases protein signals that promote angiogenesis, the development of increased blood supply to the area.
Drugs that block the receptor portion on the outside of the cell, or the tyrosine kinase portion on the inside of the cell, inhibit activity of the entire cascade.
Though the figure above highlights the intracellular activity of the tyrosine kinase inhibitors (TKIs) like tarceva (erlotinib) and iressa (gefitinib), the same concept holds true for blocking this cascade with extracellular monoclonal antibodies against the actual ligand-binding portion of EGFR.
One thing that has been unique to the story for EGFR TKIs is the special activity of this class of agents with activating EGFR mutations. We’ll cover that next.