Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin

Hsp90 is a ubiquitously expressed molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins. The benzoquinone ansamysin 17-allylamino-17demethoxygeldanamycin (17-AAG) is an anticancer drug that disrupts Hsp90 binding to its clients, causing their degradation through the ubiquitin-dependent proteasomal pathway. The protein kinase B-RAF is mutated in similar to 7% of human cancers. The most common mutation (similar to 90%) is B-V600E-RAF, which has constitutively elevated kinase activity, stimulates cancer cell proliferation, and promotes survival. Here, we show that B-V600E-RAF is an Hsp90 client protein that requires Hsp90 for its folding and stability. (V600E)BRAF is more sensitive to degradation by 17-AAG treatment than B-WT-RAF and we show that the majority of the other mutant forms of B-RAF are also sensitive to 17-AAG-mediated proteasomal degradation. Our data show that B-RAF is an important target for 17-AAG in human cancer. (Cancer Res 2005; 65(23): 10686-91).