The novel IKK2 inhibitor LY2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of NF-κB.

Abstract

To evaluate the pharmacologic activity of a novel inhibitor of IκB kinase β (IKK2), LY2409881, in preclinical models of B- and T-cell lymphoma, as a single agent and in combination with histone deacetylase (HDAC) inhibitors. The in vitro activity of LY2409881 was determined using an ATP-based growth inhibition assay and flow cytometric assay of apoptosis in lymphoma cell lines. The in vivo activity of LY2409881 was determined using SCID-beige xenograft mouse model. The mechanism of action was determined using immunoblotting, immuofluorescence, and electrophoretic mobility shift assay. Synergy of LY2409881 with other drugs active in lymphoma was determined by calculating relative risk ratio (RRR) and combination index (CI). LY2409881 inhibited constitutively activated NF-κB, and caused concentration- and time-dependent growth inhibition and apoptosis in lymphoma cells. In models of diffuse large B-cell lymphoma (DLBCL), the cytotoxicity of LY2409881 correlated with the overall activation status of NF-κB, but not simply in a pattern predicted by the cell-of-origin classification of these cell lines. LY2409881 was safe to mice at three dose levels, 50, 100, and 200 mg/kg, all of which caused significant inhibition of tumor growth. LY2409881 suppressed the activity of the NF-κB subunit p65 in lymphoma cells treated by the HDAC inhibitor romidepsin, underlying a potential mechanism of the marked synergy observed of these two drugs. Collectively, these data strongly suggest that targeting the NF-κB pathway in combination with romidepsin could represent a novel and potent regimen for the treatment of B- and T-cell lymphoma.