Data from A Purine Scaffold HSP90 Inhibitor BIIB021 Has Selective Activity against KSHV-Associated Primary Effusion Lymphoma and Blocks vFLIP K13-Induced NF-κB

Abstract

<div>Abstract<p><b>Purpose:</b> 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 the NF-κB 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.</p><p><b>Experimental Design:</b> We have analyzed the effect of HSP90 inhibitors on the survival and proliferation of PEL cells and on the activity of the NF-κB pathway.</p><p><b>Results:</b> 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 PEL was 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 constitutive NF-κB activity present in PEL cells, in part, by blocking the interaction of vFLIP K13 with the IKK complex subunits. In a xenograft model of PEL, BIIB021 significantly reduced tumor growth.</p><p><b>Conclusion:</b> BIIB021 blocks constitutive NF-κB activity in PEL and shows preferential antitumor activity against PEL <i>in vitro</i> and <i>in vivo</i>. BIIB021 may be a promising agent for treatment of PEL. <i>Clin Cancer Res; 19(18); 5016–26. ©2013 AACR</i>.</p></div>