Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: therapeutic implications

Nuclear factor-kappa B (NF-kappa B) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-kappa B signaling cascades, I kappa B kinase alpha (IKK alpha) and IKK beta are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKK alpha versus IKK beta in MM cell lines. All MM cell lines have constitutive canonical NF-kappa B activity, and a subset of MM cell lines shows noncanonical NF-kappa B activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-kappa B activity. IKK beta inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-kappa B pathway. Although IKK alpha knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-kappa B activation. Importantly, IKK alpha down- regulation decreases expression of beta-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKK beta inhibitor enhances the growth inhibition triggered by IKK alpha down-regulation in MM cells with both canonical and noncanonical NF-kappa B activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM. (Blood. 2009; 113: 5228-5236)