Introduction
In addition to orchestrating immune and inflammatory responses, NF-κB transcription factors play a crucial role in oncogenesis (Staudt, 2010). NF-κB is aberrantly activated in a wide range of human cancers, in which it promotes survival and malignancy by upregulating antiapoptotic genes (Staudt, 2010; DiDonato et al., 2012). The paradigm of these cancers is multiple myeloma (MM), an incurable malignancy of plasma cells (PCs), accounting for nearly 2% of all cancer deaths (Kuehl and Bergsagel, 2002). The current treatment for MM includes chemotherapy and steroids combined with newer agents, such as proteasome inhibitors and immunomodulatory drugs (IMiDs), whereas stem cell transplantation is an option for select patients. These treatments, however, generally achieve only temporary remissions, and so most patients eventually relapse and/or develop drug resistance (Rajkumar, 2011; Mahindra et al., 2012). Thus, despite the introduction of new treatments, the management of myeloma patients remains a major medical problem. Consequently, there is a need for more effective therapeutic approaches targeting defined oncogenetic events in MM.
Compelling evidence has established the paramount importance of aberrant NF-κB signaling in MM pathogenesis (Staudt, 2010; DiDonato et al., 2012). The most conclusive affirmation of this key role of NF-κB in MM has come from the discovery of a diverse array of genetic alterations targeting components of the NF-κB pathway, such as the upstream activator, NF-κB-inducing kinase and the inhibitor tumor necrosis factor receptor-associated factor 3, in about 20% of MM patients and more than 40% of MM cell lines (Annunziata et al., 2007; Keats et al., 2007; Demchenko et al., 2010; Chapman et al., 2011). Irrespective of their nature, these oncogenic lesions lead to constitutive activation of both main pathways of NF-κB signaling, namely, the classical and alternative pathways (Keats et al., 2007; Annunziata et al., 2007; Staudt, 2010; DiDonato et al., 2012). In fact, even in those patients with no recognizable NF-κB-pathway mutations, MM cells constitutively engage these pathways via stimuli emanating from the tumor microenvironment (Hideshima et al., 2005; Staudt, 2010). Consequently, more than 80% of all primary MM cells and the vast majority of MM cell lines display nuclear accumulation of NF-κB and high NF-κB target gene signature, leading to NF-κB-pathway addiction and sensitivity to apoptosis upon IκBα kinase (IKK) β/NF-κB inhibition (Staudt, 2010).
Collectively, these findings provide a strong rationale for therapeutically targeting the NF-κB pathway in MM. However, despite the pharmaceutical industry’s aggressive effort to develop specific NF-κB or IKKβ inhibitors for indication both within and outside of oncology, no such inhibitor has been clinically approved, because of the preclusive toxicities associated with the global suppression of NF-κB (DiDonato et al., 2012). Similarly, proteasome inhibitors with clinical indication in MM, such as bortezomib, inhibit many essential cellular pathways that rely on proteasome function, among which is the NF-κB pathway, and, furthermore, target these pathways in normal and cancer cells alike, thus resulting in a low therapeutic index and dose-limiting toxicities (Richardson, 2010; Chen et al., 2011). Indeed, it is unclear that the clinical activity of proteasome inhibitors in MM, as well as that of IMiDs, which too have broad molecular specificity and can affect NF-κB signaling, is due to the inhibition of NF-κB (Staudt, 2010; Chen et al., 2011; McCurdy and Lacy, 2013).
The conundrum with conventional NF-κB-targeting strategies has been how to achieve cancer cell specificity, given the ubiquitous nature and pleiotropic physiological functions of NF-κB (DiDonato et al., 2012). Because a key pathogenetic activity of NF-κB in MM is to block apoptosis through the induction of target genes, an attractive alternative to globally targeting NF-κB would be to block the nonredundant, cancer-specific downstream effectors of the NF-κB survival function; these effectors, however, are not known. To develop a strategy for inhibiting the NF-κB pathway in a cancer-selective manner and, thus, exploiting its therapeutic potential, we therefore sought to delineate the mechanism(s) underlying the pathological survival activity of constitutive NF-κB signaling in MM. Further, we sought to develop a pharmacological inhibitor of this mechanism(s) in order to kill MM cells effectively and without toxicity to normal cells.