The Raf family includes three members, of which B-Raf is frequently mutated in melanoma and other tumors. We show that Raf-1 and A-Raf require Hsp90 for stability, whereas B-Raf does not. In contrast, mutated, activated B-Raf binds to an Hsp90 -cdc37 complex, which is required for its stability and function. Exposure of melanoma cells and tumors to the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in the degradation of mutant B-Raf, inhibition of mitogen-activated protein kinase activation and cell proliferation, induction of apoptosis, and antitumor activity. These data suggest that activated mutated B-Raf proteins are incompetent for folding in the absence of Hsp90, thus suggesting that the chaperone is required for the clonal evolution of melanomas and other tumors that depend on this mutation. Hsp90 inhibition represents a therapeutic strategy for the treatment of melanoma.17-allylamino-17-demethoxygeldanamycin ͉ cdc37 ͉ melanoma I n the last several years, it has become clear that the Ras͞Raf͞ mitogen-activated protein kinase (MAPK)͞extracellular signalregulated kinase kinase (MEK)͞MAPK signaling pathway is mutationally activated in most melanomas. One member of the Ras family, N-Ras, is mutated in Ϸ25% of melanomas (1), whereas mutations in the H-ras and K-ras genes are rare (2). The Raf gene family (Raf-1, A-Raf, and B-Raf) encodes closely related serine͞ threonine protein kinases that are important effectors of Ras activation. However, no mutations in the Raf gene were found until recently, when Davies et al. (3) showed that Raf-1 and A-Raf are rarely mutated but that mutations in the B-Raf gene are common in human cancer, especially in melanoma.Refs. 3 and 4 showed that B-Raf is mutated in Ϸ70% of human melanomas, 35-70% of papillary thyroid carcinomas, and less commonly in lung and colorectal carcinomas. Mutations are almost always in the B-Raf kinase domain and, in melanomas, the vast majority are V600E missense mutations (3). Marais and coworkers (5) have shown in heterologous systems that the V600E mutation leads to activation of B-Raf kinase.The frequency and activating nature of the B-Raf mutations suggest that they have an important role in the biology of melanoma and perhaps other tumors in which they have been detected. Moreover, small interfering RNA against mutated B-Raf but not Raf-1 inhibits the transformed phenotype of melanoma cells harboring B-Raf mutations (6, 7). N-Ras and B-Raf mutations seem to be mutually exclusive in melanoma, suggesting that they make similar contributions to transformation and that activation of this pathway is a key event in the development of this disease (3,8).Together, these data suggest that inhibition of B-Raf͞MEK͞ MAPK signaling could be a powerful means for treating melanomas and other tumors with B-Raf mutation. There is no validated therapy that potently inhibits mutated B-Raf function in patients. Selective inhibitors of MEK have been developed and have antitumor activity in xenograft models of melanoma (9). Putative Raf inhibitor is ...
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