RAF translocations expand cancer targets

Abstract

Chromosomal translocations can promote cancers by eliciting the expression of fusion genes with oncogenic activity. The identification of translocations affecting RAF genes in prostate and gastric cancers and melanoma provides compelling evidence for the key role of RAF signaling in a subset of these cancers and suggests possible new avenues for personalized cancer therapy.

Figure 1

RAF fusion genes in prostate and gastric cancer and melanoma. The RAF family of protein kinases are activated by RAS GTPases. In turn, RAF kinases activate the protein kinases MEK1 and MEK2 by serine phosphorylation at two sites within the activation segment of the kinase domain. MEK1 and MEK2 activate the ERK MAP kinases by phosphorylation of a threonine and a tyrosine residue in the activation segment of the kinase domain. Among the plethora of ERK1/2 MAP kinase targets are a number of ETS family transcription factors, which are also implicated in prostate carcinogenesis, as ETS genes are frequent targets of chromosome translocations^,. Palanisamy et al. identified fusion transcripts resulting from chromosome translocations that lead to expression of three fusion genes: SLC45A3-BRAF or ESRP1-RAF2 in prostate cancer or type 1 angiotensin II receptor–associated protein (AGTRAP) BRAF in gastric cancer. The SCL45A3-BRAF fusion mRNA encodes a 329–amino acid protein that comprises only a C-terminal fragment of BRAF. By contrast, the ESRP1-RAF2 and AGTRAP-BRAF fusions encode proteins with substantial contribution of N-terminal sequences from the RAF fusion partner. The common feature of the proteins encoded by these fusion mRNAs is the presence of a RAF kinase domain that is likely to be constitutively activated. A large number of pharmacological inhibitors of the RAF→MEK→ERK MAP kinase pathway are being developed, a subset of which are listed in the figure.