Hsp90 inhibitors are being evaluated extensively in patients with advanced
cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate
carcinomas are among those
cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these
cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against
prostate cancer cells in vitro and its inhibition of s.c.
prostate cancer xenografts, the Hsp90 inhibitor
17-AAG stimulates the intraosseous growth of PC-3M prostate
carcinoma cells. This activity is mediated not by a direct effect on the
tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast
Src kinase and promotes Src-dependent Akt activation. Both
kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor
dasatinib, the
bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer
reveromycin A, markedly reduced 17-AAG-stimulated
tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in
cancer cells, and they demonstrate that
drug-dependent modulation of the local
tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed
therapy.