Cancer Therapy: Preclinical A Purine Scaffold HSP90 Inhibitor BIIB021 Has Selective Activity against KSHV-Associated Primary Effusion Lymphoma and Blocks vFLIP K13-Induced NF-kB

Purpose: Kaposi sarcoma–associated herpes virus (KSHV)–associated primary effusion lymphomas (PEL) have extremely poor prognosis when treated with conventional chemotherapy. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) K13 binds to the IkappaB kinase (IKK) complex to constitutively activate theNF-kB pathway, which has been shown to be essential for the survival and proliferation of PEL cells. The molecular chaperone HSP90 is a component of the IKK complex and is required for its activity. Experimental Design:Wehave analyzed the effect of HSP90 inhibitors on the survival and proliferation of PEL cells and on the activity of the NF-kB pathway. Results: We show that BIIB021, a purine scaffold–based orally administrable HSP90 inhibitor, shows preferential cytotoxicity toward PEL cells as compared with non-PEL cells. The cytotoxic effect of BIIB021 against PELwas associated with induction of cell-cycle arrest and apoptosis. BIIB021 blocked the expression of a number of cellular proteins involved in the regulation of cell cycle and apoptosis. BIIB021 also blocked constitutiveNF-kB activity present in PEL cells, in part, by blocking the interaction of vFLIP K13with the IKK complex subunits. In a xenograft model of PEL, BIIB021 significantly reduced tumor growth. Conclusion: BIIB021 blocks constitutive NF-kB activity in PEL and shows preferential antitumor activity against PEL in vitro and in vivo. BIIB021 may be a promising agent for treatment of PEL. Clin Cancer Res; 19(18); 1–11. 2013 AACR.