Vemurafenib is a B-Raf

BRAF (gene)

Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...

 enzyme inhibitor

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 developed

Drug development

Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...

 by Plexxikon

Plexxikon

Plexxikon is a drug discovery company based in Berkeley, California that was co-founded in 2001 by Joseph Schlessinger of Yale University with Sung-Hou Kim of the University of California, Berkeley....

 (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma

Melanoma

Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

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Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.

Mechanism of action

Vemurafenib has been shown to cause programmed cell death

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 in melanoma

Melanoma

Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

 cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway

MAPK/ERK pathway

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...

 − if the B-Raf has the common V600E mutation.

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.

In vitro, a melanoma cell line A375 is inhibited by silencing the BRAF gene by short hairpin RNA.

Resistance

Two mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:

• The cancer cells begin to overexpress a cell surface protein PDGFRB
  PDGFRB
  Beta-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRB gene.-Interactions:PDGFRB has been shown to interact with PTPN11, NCK1, Grb2, Caveolin 1, PDGFRA, Sodium-hydrogen antiporter 3 regulator 1, RAS p21 protein activator 1, CRK, SHC1 and...
  
   creating an alternate survival pathway.
• A second oncogene called NRAS
  Neuroblastoma RAS viral oncogene homolog
  NRAS is an enzyme that in humans is encoded by the NRAS gene. It was discovered by researchers at the Institute of Cancer Research, funded by the Imperial Cancer Research Fund , and named NRAS, for its initial identification in human neuroblastoma cells.-External links:*...
  
   mutates, reactivating the normal BRAF survival pathway.

Clinical trials

In a phase I clinical study, vemurafenib was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma, and the treated group had a median increased survival time of 6 months over the control group. A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. However the regression only lasted from 2 to 18 months.

Phase I and phase II studies are ongoing, and a phase III trial has been started.

In 2010, it was also in phase I trials for colorectal cancer

Colorectal cancer

Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....

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In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. Further trials are planned including a trial where vemurafenib will be co-administered with GDC-0973, a MEK-inhibitor.

Side effects

At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgias in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, which is 91% of the MTD.