Therapeutic strategies for inhibiting oncogenic BRAF signaling

Mitogen-activated protein kinase (MAPK) activation is a common property of human cancers and is often due to activating mutations in the BRAF and RAS genes. BRAF kinase domain mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These mutations are non-overlapping in distribution with RAS mutations and are observed most frequently in melanoma but also in tumors arising in the colon, thyroid, lung and other sites. V600E BRAF mutation stimulates extracellular signal-regulated kinase (ERK) signaling, induces proliferation and is capable of promoting transformation. Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater therapeutic efficacy than the currently available systemic therapies for tumors driven by activating mutations in the MAPK pathway.