RAS and RAF signaling in melanoma: biology and therapies

Published on November 30, 2010   37 min

Other Talks in the Series: Protein Phosphorylation

0:00
My name is Richard Marais, and I work at the Institute of Cancer Research. My laboratory is primarily interested in the problem of melanoma, and specifically in the role of RAS and RAF signalling in that disease. And today, I'm going to talk about our recent studies which are aimed at trying to understand the biology of melanoma, and then using that information to apply to therapeutic approaches.
0:24
Now, melanocytes are specialised pigment cells that are primarily found in the skin, but they're also found in the eyes, the ear, the brain and the heart. And in the skin their primary function is to control skin and hair tone, but also they're very important for protecting us from UV radiation, and this is the well known "tanning response". These cells are also the precursors of melanoma, and melanoma is the most deadly form of skin cancer, because although it only accounts for about 10 percent of all skin cancers, it causes about 80 percent of skin cancer deaths. There are about 62,000 cases of melanoma in Europe every year and this results in about 12,000 deaths. In America, there are about 50,000 cases of melanoma and a consequent 8,000 deaths. Now about 80 percent of melanomas are cured by surgery, and that is possible if the disease is caught early. However, about 20 percent of patients die from metastatic disease, and in those patients, the prognosis is very poor with a median survival of 6-9 months, and a five year survival of only 5-10 percent. The risk factors for melanoma are UV radiation and your underlying genetics. But it is quite clear that UV radiation is still required even if you have a poor genetic background.
1:40
Over the last decade or so, it has become apparent that the RAS-RAF-MEK-ERK pathway is very important in melanoma. This is the classical pathway where receptor tyrosine kinases and heterotrimeric G-protein-coupled receptors activate the small GTP-binding protein RAS. Now RAS activates many different pathways, but one of these is the RAF-MEK-ERK pathway which is a cascade of three protein kinases which are linked together; And what has become apparent over the last few years, is that many of the components of this pathway are mutated in melanoma. So RAS proteins are mutated in about a quarter of melanomas: primarily NRAS, but also K and HRAS, and the protein kinase BRAF is mutated in about 44/45 percent of melanomas. Now BRAF is one of the family of three protein kinases, the other two being ARAF and CRAF, and interestingly, ARAF and CRAF are very rarely mutated in cancer and no such mutations have been found in melanoma; And this is probably due to a distinct mechanism of regulation whereby they are not converted into an oncogene by a single genetic change. The other two proteins which have been found to be mutated in melanoma are the receptor tyrosine kinase, c-Kit which is mutated in about 5 percent of melanomas, primarily in mucosal and acryl melanoma, and the heterotrimeric G-protein alpha sub-unit, GNAQ, which is also mutated in about 5 percent of melanomas, primarily in uveal melanoma.
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RAS and RAF signaling in melanoma: biology and therapies

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