Journal
CANCER CELL
Volume 30, Issue 3, Pages 485-498Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.06.024
Keywords
-
Categories
Funding
- NCI NIH HHS [P30 CA008748, R01 CA178394, T32 CA078207, P50 CA172012, P30 CA010815, P30 CA013330] Funding Source: Medline
Ask authors/readers for more resources
The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the alpha C helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including alpha C-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF(V600E) cancers, in which first-generation RAF inhibitors have been ineffective.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available