The biology and therapeutic implications of BRAF and RAS signalling in cancer


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Richard Marais
The Institute of Cancer Research, London, United Kingdom

Abstract

The small G-protein RAS in mutated about 25% of human melanomas and its downstream kinase BRAF is mutated in about another 45% of cases.  Using expression arrays, we have identified genes that regulate melanoma cell invasion and metastasis downstream of oncogenic BRAF in melanoma cells.  We are also developing drugs to target BRAF in melanoma and using gatekeeper mutants to allow the selectivity of these agents to be tested in vitro and in vivo.  We show that BRAF selective drugs inhibit pathway signalling in cells that are mutant for BRAF, whereas in cells that are mutant for RAS, these compounds drive BRAF to the plasma membrane where it forms a stable complex with CRAF and act as a scaffold to enhance CRAF activation and drive pathway activity.  We also show that in mice, oncogenic BRAF drives melanoma formation, whereas oncogenic RAS requires co-expression of kinase-dead BRAF.  These data provide insight into the biology of BRAF and RAS signalling in melanoma, reveal the potential of BRAF drugs in melanoma and highlight some of the potential off-target effects associated with drugs that target BRAF.