Cover Feature: Biochemical Characterization of Full‐Length Oncogenic BRAF^V600E together with Molecular Dynamics Simulations Provide Insight into the Activation and Inhibition Mechanisms of RAF Kinases (ChemBioChem 22/2019)

Abstract

In normal cells, BRAF is tightly regulated by upstream stimulus and negative feedback regulation loops such as inhibitory P‐loop phosphorylation; however, the mutant BRAFV600E has increased activity/oligomerization and bypasses inhibitory P‐loop phosphorylation to support the growth of cancer cells. Firstly, purified full‐length BRAFV600E has higher kinase activity than fully active wild‐type BRAF in vitro. Secondly, BRAFV600E has a higher potential to form oligomers despite the fact it has increased kinase activity independent from the side‐to‐side dimer interface. Lastly, BRAFV600E evades inhibitory P‐loop phosphorylation to impose increased activity required for tumorigenesis. More information can be found in the full paper by Z. Wang et al. on page 2850 in Issue 22, 2019 (DOI: 10.1002/cbic.201900266).

Drug resistance in targeted cancer therapies with RAF inhibitors

“…This hypothesis was further strengthened by findings that BRAF mutants with in-frame deletions in β3-αC loop have elevated dimer affinity and are resistant to RAF inhibitors [126] . However, it was also challenged by some emerging findings, which have indicated that BRAF(V600E) exists as dimers or oligomers in cells even though its dimer affinity is not as high as that of BRAF(V600E) variants with a truncated N-terminus or BRAF mutants with an in-frame deletion of β3-αC loop, and the monomeric BRAF(V600E) variant has no catalytic activity in vitro and in vivo [67,[158][159][160] . Therefore, how elevated dimer affinity of BRAF confers RAF inhibitor resistance and the root of RAF inhibitor resistance are not defined yet.…”