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

Abstract

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.

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

“…We previously reported that 17-DMAG decreases the expression of the EBV EBNA1 protein, which is required for the maintenance of the viral genome during latent infection, and showed that a nontoxic dose of the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the growth of EBV-induced lymphoproliferative disease in SCID mice (58). Interestingly, the KSHV homologue of EBNA1, LANA, was recently shown to be a Hsp90 client protein that is degraded in a proteasome-dependent manner by Hsp90 inhibitors (97). In addition, the expression level of another KSHV latency protein that pro- motes cellular transformation, K1, has also been shown to be reduced in the presence of Hsp90 inhibitors (98), as was the essential EBV transforming protein LMP1 (99).…”

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…Blocking IL-6 stymies PEL growth in preclinical models (182). Hsp90 inhibitors exhibited nanomolar EC50 against PEL and KS in three independent studies (183)(184)(185). PELs are also extremely sensitive to NF-κB pathway inhibitors such as bortezomib (186,187), and a clinical trial with adjuvant bortezomib is ongoing.…”

HSP90 Protects the Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Oncoprotein from Proteasomal Degradation To Support NF-κB Activation and HTLV-1 Replication

“…1G). HSP90 is known to translocate to the nucleus in response to stress signals or interaction with viral proteins (38)(39)(40). Taken together, HSP90 interacts with and colocalizes with Tax, and this interaction is disrupted by HSP90 inhibitors.…”