Targeting the Raf kinases in human cancer: the Raf dimer dilemma

Deborah K Morrison,David E Durrant

doi:10.1038/bjc.2017.399

Abstract

The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In particular, issues related to the dimerisation of the Raf kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. Here, we will review the importance of Raf dimerisation in cell signalling as well as its effects on Raf inhibitor therapy, and we will present the new strategies that are being pursued to overcome the ‘Raf Dimer Dilemma’.

Highlights

The Raf kinases are best known for their role in Ras pathway signalling – a pathway widely utilised to control many cellular processes, including proliferation, differentiation and survival
Many B-Raf alterations have been detected in human cancer, mutations affecting the valine residue at amino acid position 600 (V600) are most prevalent, with V600EB-Raf accounting for 80–90% of B-Raf mutations in melanoma
Subsequent studies revealed that drug resistance to vemurafenib or dabrafenib could often be attributed to cellular conditions or mutational alterations where ERK activation was dependent on Raf dimerisation

Summary

IMPORTANCE OF RAF DIMERISATION IN NORMAL AND ONCOGENIC SIGNALLING

The Raf kinases are best known for their role in Ras pathway signalling – a pathway widely utilised to control many cellular processes, including proliferation, differentiation and survival. With respect to the inhibitory feedback regulation, active ERK phosphorylates multiple components of the Ras pathway, including the Sos guanine nucleotide exchange factors and members of the Raf family. These phosphorylation events have an overall effect of attenuating signal transmission and, in the case of Raf, disrupt both Ras binding and Raf dimerisation (Dougherty et al, 2005). Mutations in receptor tyrosine kinases (RTKs), Ras family members, or the B-Raf kinase frequently hijack the proliferative and survival functions of Ras pathway signalling to drive tumourigenesis.

Targeting the Raf kinases in cancer

Negativecooperativity dimer binding

ALTERNATIVE APPROACHES TO COMBAT THE RAF DIMER DILEMMA

Findings

CONCLUSION