Hsp90 Inhibitors Are Efficacious against Kaposi Sarcoma by Enhancing the Degradation of the Essential Viral Gene LANA,of the Viral Co-Receptor EphA2 as well as Other Client Proteins

Heat-shock protein 90 (hsp90) inhibitors exhibit activity against human cancers. we evaluated a series of new,oral bioavailable,chemically diverse hsp90 inhibitors (pu-h71,auy922,biib021,nvp-bep800) against kaposi sarcoma (ks). all hsp90 inhibitors exhibited nanomolar ec50 in culture and auy922 reduced tumor burden in a xenograft model of ks. ks is associated with ks-associated herpesvirus (kshv). we identified the viral latency associated nuclear antigen (lana) as a novel client protein of hsp90 and demonstrate that the hsp90 inhibitors diminish the level of lana through proteasomal degradation. these hsp90 inhibitors also downregulated epha2 and ephrin-b2 protein levels. lana is essential for viral maintenance and epha2 has recently been shown to facilitate kshv infection; which in turn feeds latent persistence. further,both molecules are required for ks tumor formation and both were downregulated in response to hsp90 inhibitors. this provides a rationale for clinical testing of hsp90 inhibitors in kshv-associated cancers and in the eradication of latent kshv reservoirs. © 2012 chen et al.