The Biology and Therapeutics of RAS and BRAF Signalling in Melanoma

The Biology and Therapeutics of RAS and BRAF Signalling in Melanoma

The Biology and Therapeutics of RAS and BRAF Signalling in Melanoma

Thursday, October 20, 2011 - 4:00pm

The Wistar Institute, 3601 Spruce Street, Philadelphia, PA

The Biology and Therapeutics of RAS and BRAF Signalling in Melanoma

Richard Marais, Ph.D., FMed Sci
Professor of Molecular Oncology
The Institute of Cancer Research

Dr. Marais describes his work:

The focus of our work is cell signalling in melanoma, with particular emphasis on the role of BRAF and RAS. We have developed mouse models of melanoma driven by these oncogenes and use cell biological approaches to study how cell signalling downstream of BRAF and NRAS drives melanomagenesis and melanoma progression.

Recent studies have demonstrated that BRAF induces melanoma cell invasion by downregulating the cGMP specific phosphodiesterase PDE5A. We have also shown that whereas BRAF inhibitors block signalling in BRAF mutant melanoma cells, they drive paradoxical activation of the pathway in RAS mutant cells. This is because RAF inhibitors drive the formation of RAF dimers in which one partner is drug-bound and the other drug-free.  The drug bound partner acts as a scaffold or induces a conformational change that drives activation of the drug-free partner, leading to pathway hyper-activation and tumourigenesis.  This paradoxical activation is the basis of some of the side effects that occur in melanoma patients treated with BRAF-targeting drugs, providing mechanism-based strategies to block their development.