Targeting oncogenic BRAF in human cancer

Abstract

Mitogen Activated Protein Kinase (MAPK) pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. BRAF missense mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These kinase domain mutations, which are non-overlapping in distribution with RAS mutations, are observed most frequently in melanoma but are also common in tumors arising in the colon, thyroid, lung, and other sites. Supporting its classification as an oncogene, (V600E)BRAF stimulates 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 the 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 efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations of MAPK pathway components. Early clinical results with the BRAF-selective inhibitors PLX4032 and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF.

Figure 1. The MAP kinase signaling pathway

The MAP kinase pathway is activated in human tumors by the binding of ligand to receptor tyrosine kinases (RTKs), by constitutive activation of an RTK, by loss of NF1 function, or by mutations in RAS, BRAF and MEK1. Phosphorylation and thus activation of ERK regulates transcription of target genes which promote cell cylce progression and tumor survival. The ERK pathway contains a classical feedback loop in which the expression of feedback elements such as SPRY and DUSP family proteins are regulated by ERK (dashed grey lines). Selected agents that target the MAP kinase and PI3 kinase/AKT pathway are shown (red).