BRAF as therapeutic target in melanoma

Abstract

BRAF is a member of the RAF kinase family, which acts in the ERK/MAP kinase pathway, a signalling cascade that regulates cellular proliferation, differentiation and survival. Single point mutations can turn BRAF into an oncogene, but there appears to be a cell type/tumour specific relevance for BRAF kinase-activating mutations, since they are found predominantly in cutaneous melanoma. With the success of targeting other oncogenic kinases such as BCR-ABL, KIT or members of the epidermal-growth factor receptor (EGFR) family in other cancers, the expectations were high when the first RAF kinase-targeting drug (sorafenib) reached clinical trials. However, disappointingly the first studies using sorafenib in melanoma patients did not show the anticipated single agent efficacy. More recently, the resolution of the BRAF crystal structure has led to the development of better, more specific BRAF inhibitors such as the Plexxikon compound, PLX4032, which induced a dramatic response rate in phase I trials, validating BRAF as a clinically relevant target. In addition, our understanding of melanoma biology and the role BRAF is playing therein has improved significantly. The complexity in the ERK/MAP kinase pathway including important feedback mechanisms has been dissected, and the relevance of cross-talks with other signalling pathways has been revealed, suggesting strategies for the design of improved, more efficient combinatorial therapies. This review highlights the relevance of BRAF and the ERK/MAP kinase pathway for melanoma cell biology and discusses some of the recent advances in both, the understanding of BRAF function in melanoma and the development of improved BRAF targeting inhibitors.