Raf kinases in cancer–roles and therapeutic opportunities

Abstract

Raf are conserved, ubiquitous serine/protein kinases discovered as the cellular elements hijacked by transforming retroviruses. The three mammalian RAF proteins (A, B and CRAF) can be activated by the human oncogene RAS, downstream from which they exert both kinase-dependent and kinase-independent, tumor-promoting functions. The kinase-dependent functions are mediated chiefly by the MEK/ERK pathway, whose activation is associated with proliferation in a broad range of human tumors. Almost 10 years ago, activating BRAF mutations were discovered in a subset of human tumors, and in the past year treatment with small-molecule RAF inhibitors has yielded unprecedented response rates in melanoma patients. Thus, Raf qualifies as an excellent molecular target for anticancer therapy. This review focuses on the role of BRAF and CRAF in different aspects of carcinogenesis, on the success of molecular therapies targeting Raf and the challenges they present.

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

“…[65][66][67][68] A recent study demonstrated the utility of cancer genomic profiling by linking such mutations in TSC2 to improved survival for UC patients under everolimus treatment. 69 Amplification of RAF1, which has been linked to high-grade tumor, advanced-stage tumor and poor survival in UC, [70][71][72] was also observed in the series, and can be targeted by kinase inhibitors such as Sorafenib, a multikinase inhibitor whose targets include the Raf1 protein (CRAF). Sorafenib has been approved for use in renal cell carcinoma and hepatocellular carcinoma and is under investigation in clinical trials in multiple solid tumor types.…”

Carnosine and cancer: a perspective

“…ERK is a member of the mitogen activated protein kinases (MAPK) with at least 180 substrates identified to date [for a review see (Niault and Baccarini 2010)]. Accordingly, ERK signalling regulates many functions including cell survival (Xia et al 1995) and proliferation in a broad range of human tumours [for review see (Maurer et al 2011)]. Scavenging of radicals by carnosine may, therefore, reduce ERK signalling in tumour cells followed by impaired survival and proliferation.…”

Raf Kinase Inhibitor Protein (RKIP) Dimer Formation Controls Its Target Switch from Raf1 to G Protein-coupled Receptor Kinase (GRK) 2

“…These proteins are ubiquitously expressed kinases with a prominent role in the regulation of cellular functions and, thus, need to be tightly regulated. The Raf/MEK/ERK cascade is involved in cancerogenesis and in development of cardiac hypertrophy (21,22). This cascade coordinates gene expression, differentiation, proliferation, and cell survival.…”