The Therapeutic Potential of Targeting NIK in B Cell Malignancies

Abstract

NF-κB-inducing kinase (NIK) is a key player in non-canonical NF-κB signaling, involved in several fundamental cellular processes, and is crucial for B cell function and development. In response to certain signals and ligands, such as CD40, BAFF and lymphotoxin-β activation, NIK protein stabilization and subsequent NF-κB activation is achieved. Overexpression or overactivation of NIK is associated with several malignancies, including activating mutations in multiple myeloma (MM) and gain-of-function in MALT lymphoma as a result of post-translational modifications. Consequently, drug discovery studies are devoted to pharmacologic modulation of NIK and development of specific novel small molecule inhibitors. However, disease-specific in vitro and in vivo studies investigating NIK inhibition are as of yet lacking, and clinical trials with NIK inhibitors remain to be initiated. In order to bridge the gap between bench and bedside, this review first briefly summarizes our current knowledge on NIK activation, functional activity and stability. Secondly, we compare current inhibitors targeting NIK based on efficacy and specificity, and provide a future perspective on the therapeutic potential of NIK inhibition in B cell malignancies.

Keywords: B cell malignancies; NIK; in vitro; in vivo; small molecule inhibitors; therapeutic targets.

Figure 1

Schematic overview of non-canonical signaling pathway and NIK regulatory mechanisms. In resting cells, NIK forms a complex with TRAF2/3 and cIAP1/2, which leads to the continuous ubiquitination and proteasomal degradation of NIK. Upon ligand binding, TRAF3 is recruited to the receptor, where TRAF2 induces ubiquitination of cIAP1/2 which in turn induces ubiquitination of TRAF3. As a result, TRAF3 is degraded and NIK is stabilized. After NIK stabilization, NIK is able to phosphorylate the IKKα complex to induce activation. After direct phosphorylation of the precursor p100 by both NIK and the IKKα complex, p100 will undergo proteasomal processing into the active subunit p52, which together with RelB may translocate to the nucleus to activate target genes.