Vemurafenib

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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.

How does vemurafenib work? 
When a cell surface receptor receives a signal, a structural change in the receptor enables it to interact with and activate a protein called RAS. RAS, in turn activates BRAF, which then turns on a protein called MEK. The MEK protein activates yet another protein called ERK, which then sets a whole series of responses in motion. These include regulating the activities of a range of additional proteins and increasing or decreasing the levels of some proteins. These activities combine to promote cell growth, division, and survival.

BRAF activates MEK through its protein kinase activity, which enables it to carry out a chemical reaction that alters MEK’s structure. Normally, the protein kinase activity of BRAF is very low unless it is activated by RAS. A mutation of the DNA that carries the genetic code for BRAF results in a change in just one of its building block amino acids, the 600th in the protein chain. The most common mutation changes the normal amino acid, valine (V), into glutamic acid (E), so it is frequently designated the V600E mutation. The second most common mutation changes valine to lysine (K), so it is designated V600K. Both of these mutations make BRAF’s protein kinase activity permanently very high, so it no longer depends on signals coming from the receptor through RAS. An obvious way to stop the mutant BRAF is to design a drug that attaches to the protein and blocks its kinase activity. Vemurafenib was specifically designed to block the activity of the V600E mutant form of BRAF. It also has some activity against the V600K mutant in laboratory tests.

How is vemurafenib currently used in the clinic?
BRAF mutations are found in 7 to 8% of all human cancers. However, they are particularly prevalent in melanoma (50 to 60% of all tumors), papillary thyroid carcinomas (30 to 50%), and colorectal carcinomas (5 to 15%). Because melanoma responds poorly to most other forms of chemotherapy, the first clinical trials of vemurafenib focused on that cancer. Clinical trials comparing vemurafenib to dacarbazine, the most commonly used drug for melanoma, were very encouraging. Among patients with advanced melanoma carrying the V600E mutation, 53% demonstrated a response to vemurafenib, compared to only 8% that responded to dacarbazine. Vemurafenib increased the average overall survival of these patients to 13.6 months compared to 10 months with dacarbazine. Note that the survival of patients taking dacarbazine is higher than expected, because many of these patients were switched to vemurafenib during the course of the clinical trial when it became clear that vemurafenib was the more effective drug. As a result of these positive results, the United States Food and Drug Administration (FDA) approved vemurafenib in 2011 for use in patients with metastatic melanoma or melanoma that cannot be treated surgically. However, use of vemurafenib was approved only for patients with tumors carrying the V600E mutation. Vemurafenib has shown some effectiveness against melanomas with the V600K mutation, but the results are not as impressive, and the number of patients studied so far is small. 

Vemurafenib has also been tested in patients with colorectal cancer, but the results of those trials have been discouraging. Clinical trials of the drug for thyroid and other cancers are ongoing. Information on these trials can be found at the National Institutes of Health website

What is vemurafenib resistance?
When patients carrying a V600E BRAF mutant melanoma take vemurafenib, almost all show at least some shrinkage of the tumor, and many experience a large decrease in the total amount of tumor present in the body. Unfortunately, in nearly all patients the tumor begins to grow again, usually after six to eight months of therapy. The reasons for this new resistance to the drug are often complicated. In some patients, the tumor develops a mutation in the gene for the RAS protein. The result is excessive activity of RAS that is sufficient to overcome the effects of vemurafenib on BRAF. In other cases, a second mutation of the BRAF protein or increases in the amount of BRAF V600E enable the cancer cell to overcome the inhibition by vemurafenib. Other ways of developing resistance are by activating different proteins that activate MEK, or using totally different protein systems to transmit signals into the cell, thereby completely bypassing the need for BRAF. Scientists are currently working to find ways to combat resistance in tumors. Currently, the most promising approach is to combine vemurafenib with a drug that blocks the activity of MEK. Since many vemurafenib-resistant tumors still rely on MEK and its ability to activate ERK, blocking MEK and BRAF together may prevent resistant cells from developing. In fact, this approach has been tested using dabrafenib, a drug very similar to vemurafenib, combined with a second drug, trametinib, which attaches to MEK and blocks its activity.  Clinical trials of this combination have been highly encouraging, and additional trials are now ongoing for similar combinations using vemurafenib.

What are the side effects of vemurafenib?
Most patients taking vemurafenib tolerate the drug well. The fact that the drug does not block normal BRAF means that its effects on healthy cells of the body are small. However, some side effects do occur. These include rash, fatigue, nausea, muscle aches, and sensitivity of the skin to light. Often, these side effects can be relieved by reducing the dose of the drug. An additional rather surprising side effect, which is seen in up to 30% of patients, is the appearance of new skin tumors that are not melanoma. These are usually a form of squamous cell carcinoma, and they most often appear at 6 to 24 weeks after starting vemurafenib therapy. Although these are cancers, they are rarely aggressive, and are easily removed and cured. However, patients taking vemurafenib and their doctors must be watchful for their appearance, so they can be treated early.
 


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).

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