Vemurafenib (Zelboraf) belongs to a class of drugs known as protein kinase inhibitors. It works by blocking the function of an abnormal form of a protein called BRAF. The RAF proteins were discovered through studies of viruses that cause cancer in mice. The name RAF comes from the “Rapidly Accelerated Fibrosarcoma” protein that was found in one of these viruses. There are three normal versions of the RAF proteins in humans, designated ARAF, BRAF, and CRAF. In healthy cells, the RAF proteins work together with other proteins to transmit signals received by cell surface receptors into the cell. Signal transmission by RAF proteins plays an important role in growth and development prenatally and during childhood and helps to maintain normal replacement of old and damaged cells in adults. However, mutation of the DNA that carries the genetic code for BRAF can change the protein so that its activity is very high and out of control. The result is that the cell receives excessive signals to grow and divide, leading to the hallmark behavior of cancer.
Terminology
Protein Kinase Inhibitors – Protein kinase inhibitors make up a class of drugs that attach to and block the action of a group of proteins called protein kinases. Protein kinases cause a chemical reaction that alters the structure and function of another protein. These changes play a role in transmitting signals from the outside to the inside of the cell. Often, the signals transmitted by the action of protein kinases are involved in the regulation of cell growth and division. Thus, excessive protein kinase activity can lead to the out-of-control growth found in cancer. There are many protein kinases, and each inhibitor is usually designed to block just one or a few of them. As a result, a patient can be treated with the inhibitor that blocks only the protein kinase that functions abnormally in his/her cancer. This “targeted” approach allows all of the other protein kinases to carry out their usual functions throughout the body, minimizing unwanted side effects.
Protein – Proteins are large molecules that carry out a wide variety of functions in a cell, including structure, motility, signaling, and catalysis (speeding up and controlling chemical reactions). Proteins are made from 20 building blocks called amino acids. The synthesis of a protein begins by forming a long chain of amino acids. The identity of each amino acid at every position in the chain is unique for each protein and is specified by the genetic code in the cell’s DNA. Once the amino acid chain is formed, it coils and folds into a three-dimensional structure that is necessary for the protein’s function.
BRAF – BRAF and its cousins, ARAF and CRAF, comprise a family of proteins that help to transmit signals from receptor proteins at the surface of the cell to the interior of the cell. The RAF name comes from “Rapidly Accelerated Fibrosarcoma” because the protein was originally discovered through work on a virus that causes fibrosarcomas in mice. BRAF is a protein kinase that acts by carrying out a chemical reaction that changes the structure and function of another protein. Normally, BRAF’s protein kinase activity in the cell is low. It is activated when a cell surface receptor receives a signal, leading to the activation of a protein called RAS. RAS, in turn activates BRAF. BRAF’s job is to activate another kinase, MEK, which then activates yet another kinase called ERK. ERK then regulates the activities of a large number of proteins in the cell that control growth, division, and survival. A mutation in the DNA that carries the genetic code for BRAF may alter the protein so that it is permanently active. The result is out-of-control activation of MEK and ERK, leading to excessive cell growth and division. Note that, although ARAF and CRAF are very similar to BRAF in structure and function, it is very rare to find mutations that activate these proteins in cancer.
Signals – In any plant or animal that is made up of more than one cell, communication between cells is extremely important. Often, this communication occurs in the form of chemical signals that are produced by one cell and carried to another one, either close by, or at some distance away. To receive these signals, cells have specialized proteins, called receptors, to which the signals attach. Each chemical signal has its own specialized receptor. Once the signal molecule attaches to its receptor, the receptor’s structure is altered, and it causes chemical reactions to occur inside of the cell. These reactions lead to alterations in the function of other proteins. Signaling molecules that tell the cell to grow and divide, their receptors, and/or proteins that transmit the signals into the cell frequently function abnormally in cancer.
Receptor – A receptor is a protein that is usually found on the surface of cells. Its job is to transmit signals from the outside to the inside of the cells. The signals come in the form of smaller proteins or other molecules that attach to the receptor on the outer surface of the cell. Following this attachment, changes occur in the structure of the receptor that enable it to alter the functions of other proteins inside of the cell.
Mutation – A mutation is an alteration of the chemical structure of DNA. Such an alteration in the region that carries the code for a protein can lead to the synthesis of an abnormal form of the protein. In most cases, mutations lead to loss of function of the protein, but increased activity can also occur. Cancer cells carry large numbers of mutations, many of which lead to abnormal protein function that results in out-of-control cell growth and division.
DNA – DNA (deoxyribonucleic acid) is a very long molecule found in the nucleus of cells. It is made up of a chain of four subunits, adenine, guanine, cytosine, and thymine. The order of the subunits in the chain serves as a chemical code that tells the cell how to make all of the proteins necessary for life. There is a specific region of DNA that carries the code for each protein. This region is referred to as the gene for that protein.
Genetic Code – This is the order of adenine, guanine, cytosine, and thymine subunits in DNA that specifies how the cell will make all of the proteins needed for life. For every protein, there is a corresponding region in DNA that carries the unique code for that protein.
RAS – RAS is a protein that plays a role in transmitting signals from some cell surface receptors into the interior of the cell. Its name comes from “RAt Sarcoma” because it was originally discovered through studies of viruses that cause sarcomas in rats. Normal RAS proteins are activated when they interact with a cell surface receptor that has received a signal. Activated RAS proteins then bind to RAF proteins and cause them to become activated. There are three RAS proteins in human cells, HRAS (Harvey RAS) and KRAS (Kirsten RAS), both named for the virus in which they were discovered, and NRAS, named for its discovery in a neuroblastoma tumor. In some cancers, mutations of the DNA that carries the genetic code for one of the RAS proteins can lead to a permanently activated RAS. The result is out-of-control activation of RAF and excessive signals that tell the cell to grow and divide.
MEK – MEK is a protein kinase that is activated when its structure is altered by an activated RAF protein. MEK, in turn, alters the structure of and activates ERK. The abbreviation MEK comes from the protein’s longer name, “Mitogen-activated protein/Extracellular signal-regulated kinase Kinase. This name refers to the fact that MEK is a kinase that alters the structure of the “mitogen-activated protein/Extracellular signal-Regulated Kinase, which is the complete, long name for ERK.
ERK – ERK is a protein kinase that is activated when its structure is altered by an activated MEK protein. ERK then alters the structure of a large number of additional proteins in order to regulate their activity. These proteins play a role in cell growth, division, and survival. ERK is also sometimes called MAPK. ERK and MAPK are abbreviations for “Extracellular signal-Regulated Kinase” and “Mitogen-Activated Protein Kinase”, respectively. Both names for ERK tell something about its function. It is activated in response to signals from outside of the cell, and often these signals are mitogens, meaning that they stimulate the cells to undergo mitosis (divide).
Protein Kinase – Protein kinases are specialized proteins that are involved in regulating the activity of other proteins. They frequently play a role in transmitting signals received by receptors at a cell’s surface to the interior of the cell. Protein kinases work by causing a chemical reaction that alters the structure and function of the target protein. Often the signals transmitted by protein kinases regulate cell growth and division. Thus, excessive activity of many protein kinases can lead to the out-of-control growth found in cancer.
Amino Acids – Amino acids are the building blocks of proteins. There are twenty amino acids that are connected together in a long chain that is the foundation of the protein’s structure. The order of the amino acids and length of the chain are unique for each protein. Once the amino acid chain is made, it curls and folds into a distinctive shape that is dependent on the order of amino acids in the chain. The correct three-dimensional shape of the protein is required for proper function. Changes in the identity of the amino acids in the chain or chemical alteration of the amino acids can lead to increases, decreases, or total loss of the protein’s activity.
Melanoma – A cancer of the pigmented cells (melanocytes), usually of the skin. Melanomas can also arise in the mucous membranes and the eye. Although melanoma is the least common form of skin cancer, over 76,000 new cases are diagnosed in the United States per year. Fortunately, most melanomas are found early and can be cured by surgical removal. However, advanced stage melanomas are extremely difficult to treat, resulting in over 9,000 deaths per year. The primary cause of melanoma is exposure to ultraviolet radiation (sunlight).
Dacarbazine (DTIC-Dome) – Dacarbazine is a cancer chemotherapy drug that has been in use in the United States since its Food and Drug Administration approval in 1975. It works by damaging cell DNA. Since cancer cells are rapidly dividing, they are heavily reliant on DNA structure and metabolism, so they are more susceptible than most normal cells to DNA damage. Dacarbazine is used to treat melanoma, Hodkin’s lymphoma, and some forms of sarcoma.
Dabrafenib (Tafinlar) – Dabrafenib is a drug used to treat cancers associated with a mutated version of the gene BRAF. It acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth (read more).
Trametinib (Mekinist) – Trametinib (trade name Mekinist) is a cancer drug. It is a MEK inhibitor drug with anti-cancer activity.
Squamous Cell Carcinoma – Squamous cell carcinoma of the skin is a kind of cancer that results from abnormal growth of cells that form the outermost layers of the skin (epidermis).