Inhibition of RAF dimers: it takes two to tango

The RAS-regulated RAF-MEK1/2-ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I1/2 ATP-competitive RAF inhibitors are effective in BRAF(V600E/K)-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the alpha C-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I1/2 RAF inhibitors. Binding of type I or I1/2 RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed paradox breakers which interrupt BRAF dimerisation through disruption of the alpha C-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins

Automated summary

The discussion in the article revolves around mutations in RAS and BRAF proteins in cancer, as well as the mechanisms of action of small molecule kinase inhibitors. The current issue is that in RAS-mutant cells, certain inhibitors can promote RAS-dependent dimerization and paradoxical activation of wild-type RAF.