A word you may keep on reading if you are a cancer patient interested in what new anticancer drugs do is “protein”. We’ve all heard of proteins in a nutritional context: we know, for example, that eating meat and legumes will greatly increase our intake of proteins, and that proteins are necessary to build muscles. So why is it then that contemporary anticancer drugs are said to target specific proteins in the body? Take for example the drug gefitinib, also known by the trade name of Iressa. It specifically targets a protein in the human body called the epidermal growth factor receptor or EGFR. How is a drug like gefitinib effective against cancer by zeroing in on a protein that is normally present in the human body?
To understand the way these drugs work, we need to understand what proteins do in the body in the first place. Critical to our understanding of proteins is what has been termed the “central dogma of molecular biology”, a basic tenet that was formulated by one of the discoverers of the helical structure of DNA, Francis Crick. Crudely termed, it can be summarized as follows: DNA makes RNA and RNA makes proteins. This is a statement about the flow of information in a cell. You can think of DNA as a giant book that contains instructions on how to build everything you might need. Just because you possess this book does not mean you will build everything in it right away: likewise, the building of “stuff” from this book is tightly regulated, so that a cell builds exactly the right kind of “stuff” it needs at any given moment. But the book exists as a central repository for all of these blueprints.
When the timing is right and the cell needs a particular “thing” made, it will essentially photocopy the necessary pages from the book to take to the construction zone. Indeed, just like carrying a 5000-page book to a construction site in order to build a door frame is unnecessary and cumbersome, the cell makes a copy of the required instructions. This copy is known as RNA. This macromolecule is very similar to DNA. Both are made of a series of four smaller molecules called “bases” which are stuck to a backbone made of sugar molecules. The difference is that DNA is more stable; RNA is more prone to degradation and exists as a cheap copy of a particular stretch of DNA. RNA has many more uses in a cell, but we will concentrate on its function as a “messenger”, a facsimile that carries the instructions to make a particular “thing”.
This “thing” is called a protein. Proteins are thus the sons and daughters of DNA, via an RNA intermediate. They are the effectors of a cell, molecules that act. You have probably heard the following names before: insulin, hemoglobin, collagen, gluten, antibodies. These are all proteins. What do proteins do in the human body?
– Transport: the protein known as hemoglobin is found in red blood cells and carries oxygen in the blood from the lungs to every cell in the body that needs it;
– Structure: the protein known as collagen plays an important role in supporting and connecting different types of tissues and organs in the body. It can be found for example in the skin, in ligaments, and in blood vessels;
– Acceleration of reactions: the protein known as DNA polymerase is crucial for the replication of DNA. Indeed, when cells divide, their DNA content needs to be divided as well without losing any of it. A copy of the entire DNA molecule is thus made by the DNA polymerase before the cells divide, so that each daughter cell has an identical “book of instructions”;
– Hormone: the protein known as insulin is secreted by the pancreas and travels all over the body to control how much sugar cells internalize;
– Receptor: the protein known as the epidermal growth factor receptor (EGFR) acts as an antenna to transmit information about the world outside the cell to the inside of the cell. If a specific molecule binds to this receptor, a whole chain of events is put into motion inside the cell, which results in increased proliferation.
It is easy to see that proteins are critical actors in the cellular world: they are modes of transportation, buildings, workers, radio signals, and radio dishes. While we constantly hear of DNA, it is the proteins, the proletariat of the cell, that do the actual work. But how do they do their work so specifically? Indeed, one of the hallmarks of proteins is that the affinity they have for their binding partners, also known as “substrates”, is very high and very specific. That antenna outside the cell only relays messages coming in at 70 megahertz, not 75.
That specificity has to do with the way in which proteins are folded and the pockets that are created. Proteins are strings of amino acids. Imagine building a snake using a pool of building blocks, like LEGOs, which come in 21 different colours. These 21 building blocks are amino acids, and the order in which they are strung together will define the kind of protein one ends up with. Some of these blocks have a positive electrical charge, while others have a negative charge and others are neutral; some like water, others abhor it. These characteristics mean that the final protein—this snake of multicoloured building blocks—will fold itself in a way which accommodates these peculiarities. Proteins thus end up twisting around, and folding themselves over, and creating little pockets here and there which can bind to specific substrates. Once a substrate binds to that pocket, it can trigger a change in the shape of the protein. That change in shape is usually the beginning of a long chain of events, like a box being passed from person to person to cover a long stretch between a truck and a storage area.
This is what happens with EGFR, a receptor protein which penetrates the cell through and through. On the outside is the antenna-like domain. When EGF is released outside the cell and makes its way to the antenna of EGFR, the entire EGFR protein becomes activated and communicates this message of “activation” to one molecule, which passes it to the next, and the next, until the net result is that the cell divides. This is a normal process in the body: certain cells need to divide at certain times. What leads to cancer is when this process stops being properly regulated and cells divide uncontrollably.
One of the many contributing factors to uncontrolled cell division is an EGFR protein which is always active. This is the equivalent of a phone which is always ringing, whether or not someone is calling. The ringing phone carries the following information: pick it up. When no one is actually calling however, this information is false. When EGFR is always active, it tells the cell to divide… and divide some more… and divide some more, even though there is no signal coming in telling the cell to divide. The EGFR protein can do this if the DNA coding for it has been mutated. A wrong base in the DNA is translated into the wrong amino acid in the protein, leading to an antenna that has a manufacturing defect.
This is where “targeted therapy” comes in: a new anticancer drug, like gefitinib, has been designed to specifically bind to EGFR and to shut its action down. EGFR is not always defective in every cancer; indeed, it seems that certain types of cancer are more prone to EGFR defects. Even then, not every patient diagnosed with this type of cancer will have an EGFR defect, which is why your oncologist may order a molecular test to determine if your tumour does indeed have a defect in EGFR, as this may help your oncologist decide on the best treatment for you.
EGFR and gefitinib are just one example of what many people are calling “personalized medicine”. Many more misbehaving protein targets have been identified in cancer research, proteins like HER2/neu, KIT, PDGFR, VGFR, and BCR-ABL. Thus, while proteins are critical for our lives, a few rogue proteins are providing oncologists with strategic targets to hit in the fight against cancer.
Featured picture by Flesh for Blood