Heat Shock Protein 90 Inhibitor BIIB021 (CNF2024) Depletes NF-kB and Sensitizes Hodgkin's Lymphoma Cells for Natural Killer Cell-Mediated Cytotoxicity

Purpose: In Hodgkin's lymphoma, constitutive activation of NF-kB promotes tumor cell survival and proliferation. The molecular chaperone heat shock protein 90 (HSP90) has immune regulatory activity and supports the activation of NF-kB in Hodgkin's lymphoma cells. Experimental Design: We analyzed the effect of HSP90 inhibition on viability and NF-kB activity in Hodgkin's lymphoma cells and the consequences for their recognition and killing through natural killer (NK) cells. Results: The novel orally administrable HSP90 inhibitor BIIB021 (CNF2024) inhibited Hodgkin's lymphoma cell viability at low nanomolar concentrations in synergy with doxorubicin and gemcitabine. Annexin V/7-aminoactinomycin D binding assay revealed that BIIB021 selectively induced cell death in Hodgkin's lymphoma cells but not in lymphocytes from healthy individuals. We observed that BIIB021 inhibited the constitutive activity of NF-kB and this was independent of IkB mutations. Furthermore, we analyzed the effect of HSP90 inhibition on NK cell-mediated cytotoxicity. BIIB021 induced the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell-mediated killing. In a xenograft model of Hodgkin's lymphoma, HSP90 inhibition significantly delayed tumor growth. Conclusions: HSP90 inhibition has direct antitumor activity in Hodgkin's lymphoma in vitro and in vivo. Moreover, HSP90 inhibition may sensitize Hodgkin's lymphoma cells for NK cell-mediated killing via up-regulation of ligands engaging activating NK cell receptors. (Clin Cancer Res 2009;15(16):5108-16)