Abstract
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 I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/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 αC-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 I½ RAF inhibitors. Binding of type I or I½ 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 αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins
Highlights
Introduction to the RASRAF–MEK1/2–ERK1/2 pathwayThe RAS-regulated RAF-MEK1/2-ERK1/2 protein kinase cascade receives and amplifies signals from growth factor receptors to drive gene expression and direct cell fate, typically promoting cell survival and proliferation [1]
The frequent mutational activation of BRAF in melanoma [23] led to the development of type I small molecule inhibitors to inhibit the constitutive activity of the most common RAF variant in cancer, BRAFV600E, which is active as a monomer in contrast with wild-type RAF which signals as a dimer. These type I compounds are successful in the treatment of BRAFV600E-mutant melanoma, but are limited by their failure to inhibit wild-type RAF; rather, they induce dimerisation of wild RAF proteins by stabilising the dimer interface, leading to paradoxical activation of MEK1/2 and thence ERK1/2 through the uninhibited dimer partner [24]
RAF has accessible binding pockets for small molecule inhibitors, and RAF inhibitors (RAFi) have been approved for the treatment of BRAFV600E/K-mutant melanoma
Summary
Introduction to the RASRAF–MEK1/2–ERK1/2 pathwayThe RAS-regulated RAF-MEK1/2-ERK1/2 protein kinase cascade receives and amplifies signals from growth factor receptors to drive gene expression and direct cell fate, typically promoting cell survival and proliferation [1]. These type I compounds are successful in the treatment of BRAFV600E-mutant melanoma, but are limited by their failure to inhibit wild-type RAF; rather, they induce dimerisation of wild RAF proteins by stabilising the dimer interface, leading to paradoxical activation of MEK1/2 and thence ERK1/2 through the uninhibited dimer partner [24].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
