MEK, BRAF, Kinase pathway – Relationships

http://www.genome.gov/27545534

Exercept:

http://www.genome.gov/27545534

Exercept:

"Melanoma is very highly mutated and is in some cases mutated approximately on an order of magnitude higher than other cancer types," said Yardena Samuels, Ph.D., an investigator in the Cancer Genetics Branch of the National Human Genome Research Institute's (NHGRI) Division of Intramural Research. Dr. Samuels is part of a National Institutes of Health (NIH)-led team studying the genetics of melanoma and is the senior author of an article in the Sept. 25, 2011, early online issue of Nature Genetics that found that mutations in the metabotropic glutamate receptor-3 (GRM3) gene cause some cases of melanoma.

This newest melanoma-causing mutation joins a growing list of culprits. In April 2011, Nature Genetics published the team's first systematic genomic probe of melanoma. Using whole-exome sequencing, a technique that deciphers just the portions of the genome that code for proteins, the researchers identified 15 new mutations that drive cancer development and one that had previously been detected. The researchers found that one of the mutated genes, GRIN2A, is mutated in 25 percent of melanoma cases. It is located in the signaling pathway for the nerve cell messenger glutamate — the same pathway as GRM3.

In the current study, the researchers focused on mutations in the largest human gene family, G protein-coupled receptors (GPCRs). The significance of the receptors coded by GPCR genes is underscored by the fact that they are the targets of more than half of drugs approved by the U.S. Food and Drug Administration (FDA). Additionally, genes in the GPCR family regulate signal pathways for cell growth, the hallmark cellular activity in cancer.

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To explore the function of this gene, the researchers studied melanoma cells that harbor the mutations. In an experiment that heightened the function of mutated GRM3, the researchers detected increased activity of a signal pathway called the MAP kinase pathway, already known to be involved in melanoma. A kinase is a type of protein enzyme that modifies other proteins to cause some particular cell function. The pathway includes a kinase known as MEK targeted by current melanoma drugs. While some targeted treatments have been effective, tumors become drug resistant within months of treatment. The pathway also is associated with the most highly mutated gene in melanoma, called BRAF.

The researchers performed a test to detect whether the cells with the newly identified mutation in GRM3 respond to the drug that inhibits the MEK pathway. They detected that mutated cells treated with a MEK inhibitor responded positively, dying off as they should rather than persistently replicating as cancer cells.

Further analysis showed that when the cells carry both a BRAF mutation and a GRM3 mutation, the inhibitor compound selectively killed the cells that had the GRM3 mutation. Dr. Samuels suggested that in some cases, failure of melanoma cells to respond to a MEK inhibitor might be due to those cells having a BRAF mutation but no GRM3 mutation. Dr. Samuels predicts that prospective genetic analysis will enable differentiation of melanoma into subclasses.

"Melanoma has been subdivided by pathological characteristics," she said. "With the advent of in-depth genetic analyses, it may become possible to classify melanoma by its genetic alterations. Based on our two recent studies, I predict several melanoma subclasses will be identified in the near future."