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Verzella, D.;  Cornice, J.;  Arboretto, P.;  Vecchiotti, D.;  Nolfi, M.D.V.;  Capece, D.;  Zazzeroni, F.;  Franzoso, G. Therapeutic Targeting of the NF-κB Pathway in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/27360 (accessed on 21 June 2024).
Verzella D,  Cornice J,  Arboretto P,  Vecchiotti D,  Nolfi MDV,  Capece D, et al. Therapeutic Targeting of the NF-κB Pathway in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/27360. Accessed June 21, 2024.
Verzella, Daniela, Jessica Cornice, Paola Arboretto, Davide Vecchiotti, Mauro Di Vito Nolfi, Daria Capece, Francesca Zazzeroni, Guido Franzoso. "Therapeutic Targeting of the NF-κB Pathway in Cancer" Encyclopedia, https://encyclopedia.pub/entry/27360 (accessed June 21, 2024).
Verzella, D.,  Cornice, J.,  Arboretto, P.,  Vecchiotti, D.,  Nolfi, M.D.V.,  Capece, D.,  Zazzeroni, F., & Franzoso, G. (2022, September 20). Therapeutic Targeting of the NF-κB Pathway in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/27360
Verzella, Daniela, et al. "Therapeutic Targeting of the NF-κB Pathway in Cancer." Encyclopedia. Web. 20 September, 2022.
Therapeutic Targeting of the NF-κB Pathway in Cancer
Edit

NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases.

nuclear factor κB NF-κB inhibitors cancer therapy targeted therapy

1. Agents Acting Upstream of IKK

From a clinical perspective, the multiplicity of stimuli that are capable of initiating distinct signaling pathways of IκB kinase (IKK) activation provide a clear opportunity for therapeutic interventions aimed at inhibiting pathway-specific mechanisms of disease that depend on downstream aberrant NF-κB activation.

1.1. TNF Receptors (TNF-Rs)

Due to their key roles in the pathogenesis of chronic inflammatory diseases and several cancer types, members of the TNF receptor (TNF-R) superfamily and their ligands have been a fertile ground for drug research [1]. Most of these receptors are also strong inducers of NF-κB signaling and, as such, have been targeted to block pathogenic NF-κB activation in cancer patients. The TNFα-specific neutralizing antibody, infliximab, which was approved in 1998 for the treatment of Crohn’s disease, is the first ever medicinal agent used in clinical settings to target the TNF-R system [1]. Infliximab and several other TNFα inhibitors, such as etanercept, adalimumab, golimumab, tocilizumab, abatacept, and certolizumab pegol, are currently also approved for the treatment of ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, and psoriatic arthritis [2]. However, their dose-limiting toxicities and significant immunosuppressive activities have precluded their clinical development in oncology [1][2]. One exception is the human TNFα analogue, tasonermin (Beromun), which has found a niche indication as adjunct therapy to sarcoma surgery to avoid amputation and for treating unresectable soft-tissue sarcoma of the limbs [3]. More recently, small molecule TNFα inhibitors, such as UCB-6786, UCB-6876, and UCB-9260, were developed to broaden the clinical utility of TNFα inhibition by reducing the high cost, side effects, and immunogenicity of TNFα-targeting biologics such as anti-TNFα antibodies [4]. These small molecules were shown to disrupt the interaction of TNFα with its receptor, TNF-R1, through an allosteric mechanism that stabilizes naturally occurring, distorted TNFα conformers, reducing TNF-R1 signaling and NF-κB activation in vitro. UCB-9260 also demonstrated good bioavailability and therapeutic activity, i.e., comparable to those of TNFα-targeting biologics, following oral administration in mouse models of TNFα-dependent inflammation [4]. Its superior oral bioavailability and selectivity for TNFα compared to other TNF-family members make UCB-9260 an attractive candidate for clinical development in oncology, as well as chronic inflammatory diseases.

1.2. Toll-Like Receptors (TLRs)

Toll-like receptors (TLRs) sense pathogen-associated molecular patterns (PAMPs) to initiate innate immune responses against infections. Except for TLR3, NF-κB activation by TLRs depends on the adaptor protein, MYD88, which is frequently targeted by gain-of-function mutations in hematological malignancies, such as DLBCL of the activated B-cell (ABC) subtype (ABC-DLBCL) and Waldenström’s macroglobulinemia (WM), where the oncogenic MYD88L265P mutation was shown to occur in over 30% and 90% of case, respectively [5]. As such, signaling intermediates of activated TLRs are attractive therapeutic targets in cancer patients, with several compounds currently in clinical use or in human trials for indications in oncology and autoimmune diseases. The synthetic oligonucleotide-based antagonist, IMO-8400, which targets endolysosomal TLR7, TLR8, and TLR9, was demonstrated to be effective in xenograft models of WM and DLBCL harboring MYD88 mutations, but it is not clear why this inhibitor is more effective in cell harboring MYD88L265P compared to those lacking MYD88 mutation. This TLR7,8,9 antagonist received orphan drug designation by the FDA in 2015 for the treatment of DLBCL [6]. However, subsequent clinical trials of IMO-8400 in patients with relapsed or refractory DLBCL and WM that carried gain-of-function MYD88L265P mutations were suspended for lack of efficacy (NCT02252146; NCT02092909; NCT02363439). Trials evaluating additional antisense oligonucleotides (such as IMO-3100 and IMO-9200) or small-molecule antagonists (such as CPG-52364) also targeting TLR7/TLR8/TLR9 in other indications have been completed, but the results have not been reported yet (NCT01622348; NCT00547014) [7]. Various agents targeting TLR2 or TLR5, such as CBLB612 (a synthetic lipopeptide agonist of TLR5), ISA-201B (a peptide agonist of TLR2), and OPN-305 (a monoclonal antibody inhibiting TLR2), also known as tomaralimab, have also been tested in phase I and II trials in patients with several cancer types, but the results have been published to date (NCT02778763; NCT03669718; NCT02363491). Additionally, the TLR3 agonist, poly-ICLC, is being investigated in human trials as an adjuvant cancer therapy (NCT04544007). Similarly, recombinant flagellin, which stimulates TLR5, is also being clinically evaluated as an adjuvant therapy in various indications, including cancer [8]. However, the most promising therapeutic strategy aimed at blocking oncogenic TLR signaling, particularly in tumors with MYD88 mutations, is the pharmacologic inhibition of the downstream protein kinases, Interleukin-1 receptor-associated kinase (IRAK)1 and IRAK4. IRAKs are adaptor proteins which are recruited, along with MYD88, to TLR/IL1R receptors upon ligand binding. These proteins can, in turn, recruit TRAF6, which then triggers IKK activation [9][10][11][12]. The strategy of targeting IRAK proteins has demonstrated a clear efficacy against non-Hodgkin’s lymphomas (NHLs), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic leukemia (T-ALL), and melanoma in preclinical settings [13][14], while small-molecule IRAK1/4 inhibitors, R835 and PF-06650833, are currently in clinical development for use in autoimmune and chronic inflammatory diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The small-molecule IRAK1 inhibitor, pacritinib, was recently approved by the FDA as an anti-cancer medication to treat myelofibrosis. Moreover, the orally available small-molecule IRAK4 inhibitor, CA-4948 (emavusertib), is currently in phase I trials in NHL, MDS, and acute myeloid leukemia (AML), as it demonstrated anti-cancer efficacy signals and a favorable safety profile in preliminary clinical data (NCT04278768; NCT03328078; NCT05178342).

1.3. Cellular Inhibitor of Apoptosis Proteins (c-IAPs)

Cellular Inhibitor of Apoptosis Proteins (c-IAP) play an important role in the regulation of both canonical and non-canonical NF-κB signaling. Following TNF-R1 engagement by TNFα, receptor-bound c-IAP1/2 contributes to the recruitment of linear ubiquitination assembly complex (LUBAC), which activates NF-κB by catalyzing the ligation of linear ubiquitin to IKKγ/NEMO and RIP1 [15]. In contrast, in the non-canonical NF-κB pathway, the ubiquitin ligase activity of c-IAP1/2 promotes constitutive NIK degradation, thereby preventing non-canonical NF-κB activation [16]. Given these dual functions of c-IAP proteins in canonical and non-canonical NF-κB signaling, c-IAP genes are targeted by both gain-of-function and loss-of-function mutations in cancer [15]. The endogenous c-IAP inhibitor, second mitochondria-derived activator of caspases (SMAC), which binds to c-IAP proteins via its AVPI tetrapeptide motif, has provided a template for the structure-based design of small-molecule inhibitors of c-IAPs [17]. ASTX660 is one of non-peptidomimetic small-molecule inhibitors of c-IAP1/2 and X-linked inhibitor of apoptosis protein (XIAP); it is currently in phase I/II trials in patients with advanced-stage solid tumors and NHLs and is also in a phase II study in patients with peripheral and cutaneous T-cell lymphoma (TCL) (NCT05082259; NCT02503423; NCT04155580; NCT04362007; NCT05403450). Furthermore, the FDA recently granted breakthrough therapy designation to the orally available SMAC mimetic c-IAP antagonist, Debio 1143 (xevinapant), as a chemio- and radio-sensitizer in the front-line therapy of patients with previously untreated, unresectable head and neck squamous cell carcinoma (HNSCC), in combination with cisplatin-based concurrent chemoradiotherapy (CRT) [18][19]. Debio 1143 is also in phase II trials in other oncological indications and was granted orphan drug designation by FDA for the treatment of ovarian cancer (NCT04122625; NCT03871959; NCT02022098) [20]. APG-1387 is another SMAC mimetic and c-IAP antagonist that is currently in phase I/II trials for the treatment of advanced pancreatic carcinoma in combination with chemotherapy, with promising initial efficacy signals and overall good tolerability (NCT04284488; NCT04643405). In preclinical models, it has shown anti-tumor efficacy against HBV-positive hepatocellular carcinoma (HCC), ovarian cancer (OC), and nasopharyngeal carcinoma, either as monotherapy or in combination with other agents [21][22][23]. At least two other small-molecule SMAC mimetics have entered phase II trials in oncology: LCL161, an orally available compound which has been tested as a monotherapy and in combination with chemotherapy in patients with high-grade serous ovarian carcinoma (HGSOC), breast carcinoma, HNSCC, and relapsed or refractory MM; and birinapant (TL32711), which was tested in combination with keytruda (pembrolizumab) in patients with microsatellite stable (MSS) colorectal carcinoma (CRC) (NCT01955434; NCT01240655; NCT01617668; NCT02890069; NCT04553692; NCT02587962; NCT01486784; NCT00993239). Although both compounds have demonstrated some efficacy in clinical trials, and LCL161 had been shown to induce a dramatic tumor regression in xenograft models of HNSCC in combination with radiotherapy [24], they also exhibited severe dose-limiting toxicities, including cytokine-release syndrome [24].

1.4. The Phosphoinositide 3-Kinase (PI3K)/AKT Pathway

The pathway mediated by Phosphoinositide 3-Kinase (PI3K) and the serine threonine kinase, AKT, also known as protein kinase B (PKB), is one of the most commonly deregulated signaling pathways in human cancers [25]. Here, PI3K/AKT signaling can be constitutively activated by several genetic mechanisms, including gain-of-function driver mutations in PIK3CA, the gene encoding the catalytic subunit, p110α; loss-of-function mutations or deletions in the tumor suppressor, PTEN; amplifications or gain-of-function mutations in genes encoding receptor tyrosine kinases (RTKs); and amplifications or gain-of function missense mutations in genes encoding one of the three AKT isoforms [26][27]. Upon activation by gene mutation or physiologic receptor stimulation, PI3K recruits AKT, which, in turn, activates its downstream effectors, mTOR and NF-κB, via direct phosphorylation of several mTOR- and NF-κB-pathway components [28], thereby promoting cell survival, proliferation, and anabolic metabolism [29][30]. As such, the PI3K/AKT signaling axis is a sought-after therapeutic target to block oncogenic signaling and downstream NF-κB activation in different cancer types. Several classes of PI3K inhibitors have been developed, including isoform-specific or dual PI3K inhibitors, pan-PI3K inhibitors, and dual PI3K/mTOR inhibitors, and are currently approved or in different stages of clinical development for the treatment of both solid and hematological malignancies [26]. In 2014, the orally available PI3Kδ inhibitor, CAL-101 (idelalisib), became the first PI3K-targeting agent to receive FDA approval for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) in combination with the anti-CD20 antibody, rituximab, and as a monotherapy for the treatment of relapsed small lymphocytic lymphoma (SLL) and follicular lymphoma (FL), after at least two lines of prior therapy [31][32]. This was followed by the approval in 2017 of BAY 80-6946 (copanlisib), a pan-class I PI3K inhibitor with preferential activity against p110α and p110δ, for the treatment of relapsed FL following at least two lines of therapy [33]. Copanlisib is currently in phase II trials for endometrial cancer, cholangiocarcinoma, and NHL, including DLBCL and marginal zone lymphoma (MZL), and in phase III trials either as monotherapy or in combination with rituximab and chemotherapy for rituximab-refractory or relapsed indolent NHL (NCT04433182; NCT04263584; NCT04572763; NCT04939272; NCT03877055; NCT03474744). However, copanlisib requires intravenous administration and has been shown to cause severe adverse effects. As such, it has yet to be approved outside the United States (US) for medicinal use. In contrast, the orally available selective PI3Kα inhibitor, BYL719 (Alpelisib), is indicated in both Europe and the US in combination with hormonal therapy (fulvestrant) for the treatment of hormone receptor (HR)-positive, HER2/neu-negative advanced or metastatic breast cancer with PIK3CA gain-of-function mutations [34]. Similarly, the oral dual PI3Kδ and PI3Kγ inhibitor, IPI-145 (duvelisib), has been granted marketing authorization in both territories for medical use in adults with relapsed or refractory CLL or SLL, following at least two liners of prior therapy [35]. Duvelisib also received approval for the treatment of adults with relapsed or refractory FL after at least two lines of prior therapy but was recently pulled from the US market by the FDA because its post-marketing requirements are no longer necessary [35]. Numerous other PI3K inhibitors, including the PI3Kδ inhibitor, INCB050465 (parsaclisib), the dual pan-class I PI3K and mTOR inhibitor, GDC-0084 (paxalisib), and the pan-class I PI3K inhibitor, GDC-0941 (pictilisib), are currently in several phase II and phase III trials, generally in combination with other agents, for a wide range of solid and hematological cancers, including HNSCC, GBM, PIK3CA-mutated breast cancer, renal cell carcinoma (RCC), DLBCL, and mantle cell lymphoma (MCL) (NCT04434937; NCT04774068; NCT03765983; NCT03970447; NCT00996892). Although improvements in patient stratification strategies and the development of rational drug combinations are rapidly extending the clinical utility of PI3K inhibitors in the treatment of cancer patients, managing adverse effects, such as infections and inflammation, as well as drug resistance, remains a challenge [26][36]. Several AKT inhibitors acting via allosteric mechanisms, such as ARQ092 (miransertib), BAY1125976, MK-2206, and TAS-117, or via ATP-competitive binding, such as AZD5363 (capivasertib) and GDC0068 (ipatasertib), are currently in clinical trials for the treatment of solid tumors, either as monotherapies or in combination with other agents (NCT04980872; NCT01147211; NCT04770246; NCT03772561; NCT04464174). To date, however, no AKT inhibitor has been clinically approved, and most of them have thus far demonstrated limited clinical utility as single agents. Several strategies are therefore being investigated to improve the efficacy of these agents by combining them with other anti-cancer therapies, such as PD-1/PD-L1 immune checkpoint inhibitors, chemotherapeutic agents, or targeted therapies, such as the PARP inhibitor, olaparib, and CDK4/6 inhibitors [37].

1.5. B Cell Receptor (BCR) Signaling

Constitutive IKK/NF-κB activation is the hallmark of many B-cell malignancies, such as HL, MM, DLBCL, and MCL [38][39]. In most of these cancers, NF-κB is frequently activated by recurrent genetic mutations targeting core components of the B Cell Receptor (BCR) complex, such as CD79A and CD79B, or upstream regulators of the canonical NF-κB pathway, such as MYD88CARD11, and TNFAIP3/A20 [40][41]. A separate group of mutations includes REL amplifications, loss-of-function mutations in NFKBIA, encoding IκBα, and gene alterations targeting components of the non-canonical NF-κB pathway, such as NIKTRAF2, and TRAF3 [40][41]. In some cases, such as in a subset of ABC-DLBCLs, NF-κB appears to be constitutively activated by non-genetic mechanisms that drive chronic BCR signaling and downstream assembly of the PKCβ and CARD11-BCL10-MALT1 (CBM) signaling complexes [40]. Consequently, in these tumors, malignant B cells frequently depend on constitutive NF-κB activation for survival and undergo apoptosis upon IKK/NF-κB inhibition [40][41]. Thus, there is a strong rationale for therapeutically targeting NF-κB in a broad range of B-cell cancers. Bruton’s tyrosine kinase (BTK) plays an essential role in driving NF-κB activation and B-cell survival downstream of the BCR, and, as such, has been targeted for therapeutic intervention in several hematological malignancies [42]
Thus, despite the clinical results obtained by targeting upstream NF-κB signaling mechanisms in the treatment of many B-cell tumors, the clinical benefits of this strategy have been limited by dose-limiting toxicities, the primary resistance of certain cancer types, and the relatively early onset of secondary drug resistance. Thus, devising alternative NF-κB-targeting approaches, potentially including the identification of actionable protein–protein interactions involved in downstream IKK activation, as well improving the selection of effective drug combinations and the precision of diagnostic assays for patient stratification, may help to enhance the healthcare benefits to patients [9].

2. Agents Targeting Core Components of NF-κB Pathway

Targeting the principal players of the NF-κB signaling pathway has been the focus of academia and pharma for the last 30 years. This enormous research effort has led to the development of several therapeutic approaches which are able to modulate the NF-κB core pathway.

2.1. IKK Complex

The IKK family is well known for its role in the activation of the NF-κB pathway during inflammation, immune cell activation, and tumorigenesis [43]. Aberrant activation of IKK family kinases is involved in different pathologic conditions including cancer, metabolic syndromes, and pathogen-associated diseases [44]. Therefore, the development of specific IKK inhibitors has been pursued by both academia and pharma since the discovery of the IKK complex. Although IKK inhibitors were proven to be effective at inhibiting the NF-κB pathway, when administered to experimental animals and human volunteers, they were found to be associated to severe toxicities due to the blockade of NF-κB ubiquitous functions [45].
IKKα/IKKβ inhibitors. Although the goal has been to develop specific IKKβ inhibitors, these compounds also block IKKα due to the amino acid sequence similarities between the two kinases. There are three classes of IKKα/IKKβ inhibitors based on their mode of action: ATP analogues (i.e., SPC-839), allosteric modulators (i.e., BMS-345541), and agents interfering with the kinase activation loops (i.e., Thiol-reactive compounds) [9][46][47], as recently reviewed elsewhere [9]. However, no IKKα/IKKβ inhibitor has been clinically approved to date. The SAR-113945 selective anti-IKKβ drug, developed for the treatment of osteoarthritis, showed promise in phase I studies but failed to be proven effective in a larger phase IIb proof-of-concept study [48]. Other IKKβ inhibitors, like AS-602868 and CHS-828, were tested in hematological or solid cancers in phase I and II clinical trials, respectively, but these studies were discontinued due to dose limiting toxicities associated with the treatment and a lack of significant tumor response [49][50]
TANK-binding kinase 1 (TBK1) and IκB kinaseε (IKKε) inhibitors. The innate immune response mediated by TLRs and MYD88 involves IκB kinase ε (IKKε or IKBKE) and TANK-binding kinase 1 (TBK1), which share high sequence identity in the kinase domain [51]. IKKε is induced in response to viral/bacterial stimuli and cytokines and is expressed exclusively in thymus, pancreas, spleen, and peripheral blood leukocytes [52]. TBK1 is constitutively expressed and, along with IKKε, controls the activation of interferon regulatory factors (IRF)3, IRF5, and IRF7 but also mediates RELA phosphorylation [47][53]. The activation of the TBK1/IKKε/IRFs pathway occurs when DNA is aberrantly localized in the cytosol due to (1) the presence of pathogen-derived DNA; (2) self-DNA leakage from the nucleus following DNA damage; or (3) DNA release from mitochondria upon oxidative stress. This activation, in turn, triggers NF-κB-mediated pro-inflammatory cytokine production during immune response to pathogens and tumors [54]. The deregulation of TBK1 activity has been associated with a wide range of human diseases including autoimmune, inflammatory, and malignant disorders [55][56][57][58]. Similarly, IKKε is overexpressed in breast cancer and OC, as well as in RA, where a recent observational study (NCT02689115) showed a higher expression of IKKε in patients with active disease than in those in clinical remission [56][57][58].
The role of IKKε and TBK1 in the pathogenesis of human diseases has led to numerous research efforts to develop specific inhibitors. Although several small molecules showed efficacy in inhibiting IKKε and TBK1, no specific molecules targeting these kinases have been evaluated in clinical trials [59]. The first TBK1 inhibitor, BX795, and MRT67307 lacked specificity and were shown to target several protein kinases [60]. In the last few years, some drugs used in the clinic with unknown mechanisms were shown to target TBK1/IKKε. Amlexanox, a drug previously approved for the treatment of asthma and allergic rhinitis, was reported to target both IKKε and TBK1 [61]. A study of the crystallographic structure of Amlexanox showed that the molecule binds to TBK1 in the aminopyridine fragment of the catalytic domain [62]. This new knowledge led to the generation of an analogue series, bearing modification at the C7 position and with improved efficacy against TBK1 [63]. In the last five years, multiple chemical series have been published [59]. Of interest, GSK8612 is highly selective for TBK1 over IKKε and could be useful to dissect the biology of TBK1. The high selectivity of GSK8612 for TBK1 was demonstrated in Ramos cells, where this small molecule inhibited TLR3-mediated IRF3 phosphorylation. In human peripheral blood mononuclear cells (PBMCs) and THP1 cells, GSK8612 was shown to be effective at micromolar concentrations and to cause the abrogation of Interferon (IFN)α and IFNβ secretion [60]. However, further in vivo investigations are required to translate this inhibitor to a clinical setting. An emerging, powerful class of therapeutic agents is Proteolysis targeting chimeras (PROTACs), which induce the degradation of proteins of interest via UPS upon interaction with E3 ubiquitin ligases [64]. The selective degradation of TBK1 using PROTACs has been explored, leading to the development of Arvinas, which was subsequently optimized, yielding an improved compound which is able to efficiently degrade only TBK1 and not IKKε in vitro [65].
NIK inhibitors. As non-canonical signaling is frequently constitutively activated in several cancers, including MM and DLBCL, by recurrent genetic alterations, including NIK amplifications and c-IAP1/2 and TRAF3 deletions, NIK has emerged as an attractive target for therapeutic interventions, given its key role in controlling IKKα phosphorylation and NF-κB2/p100 processing [9]. Over the past decade, many NIK inhibitors (i.e., staurosporine, ZINC-1601221, B022, XT2, NIK SMI1, Cpd33, HTS Hit, 7H-pyrrolo [2,3-d]pyrimidin-4-amine-containing compounds, 4H-isoquinoline-1,3-dione, N-Acetyl-3-aminopyrazoles, Mangiferin, PDB:6Z1T, and PDB-6Z1Q) have been investigated, allowing researchers to identify the key residues of NIK involved in binding with inhibitors.

2.2. Ubiquitin and Proteasome Pathway

The ubiquitin-proteasome system (UPS) is one of the main mechanisms that regulates cellular protein levels and activity; it is responsible for the degradation of over 80% of the proteins in mammalian cells [66][67]. The post-translational protein modifications carried out by the UPS modulate multiple steps during NF-κB activation. In particular, in the canonical NF-κB pathway, IκB proteasomal degradation allows the release of active NF-κB (p50/RelA), while in the non-canonical pathway, NIK/IKKα triggers the partial proteolysis of phosphorylated p100 to form p52 [68]. Given this crucial role in NF-κB activation, the ubiquitin/proteasome pathway is a target for drug development [66]. The inhibition of the UPS can be carried out by targeting different UPS components such as the ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core (20S), and the 19S proteasome regulatory particles (19S) [67].
Proteasome inhibitors. Bortezomib (20S particle inhibitor) is the first proteasome inhibitor approved by FDA for the treatment of MM, MCL, WM, non-small-cell lung cancer (NSCLC), and pancreatic cancer [69]; additionally, it is now in clinical trials for DLBCL in combination with R-CHOP and for newly diagnosed or relapsed and refractory MM-in combination therapy with dexamethasone (NCT01965977; NCT03129828; NCT05052970; NCT04140162; NCT04717700; NCT05218603; NCT03896737; NCT03733691; NCT03110562). The results from these clinical investigations demonstrated that while the addition of bortezomib to R-CHOP did not improve the outcome of patients with non-germinal center B-cell-like (non-GCB)-DLBCL treated with R-CHOP alone [70][71], the combination therapy of bortezomib and dexamethasone was effective in increasing the progression-free survival (PFS) of relapsed and refractory MM patients previously treated with lenalidomide enrolled in a phase III study [72]
Ubiquitin inhibitors. Ubiquitin (Ub) and ubiquitin-like proteins (Ubl) control many physiological processes, including protein degradation, localization, and activation by promoting post-translational modifications. Given the important role of Ub and Ubl-dependent pathways, small drugs targeting E1-activating enzymes and E3 ligases have been developed [73]. PYR-41, a ubiquitin-activating enzyme E1 inhibitor, has been demonstrated to reduce inflammation via inhibition of NF-κB-mediated secretion of proinflammatory cytokines in the lungs of septic mice [74]. It was also shown to block angiotensin II-induced activation of dendritic cells in autoimmune diseases [75]. MLN4924 (Pevonedistat) was discovered to be a potent inhibitor of NEDD8 activating enzyme (NAE) which is able to induce apoptosis in vitro and suppress tumor growth in vivo. NAE is an important molecule that controls the turnover of several proteins by regulating the activity of cullin-RING-E3 ubiquitin ligases [76]. A phase Ib study of MLN4924 in combination with standard-of-care chemotherapies for the treatment of patients with solid tumors demonstrated that this therapeutic regimen was well tolerated, and no drug-related adverse events were reported [77].
The NF-κB signaling pathway is activated by LUBAC, comprising the HOIL-1L, HOIP, and SHARPIN subunits [78]. Abnormal LUBAC activity was observed in several disorders, including ABC-DLBCL [79]. Recently, multiple LUBAC inhibitors (i.e., JTP-0819958 (HOIPIN-1) and its derivates) have been tested in vitro, where they showed inhibitory effects on the NF-κB pathway activation [80]. An in vitro assay identified Bendamustine as the best selective HOIP ligases inhibitor [81]. Bendamustine showed clinical efficacy with acceptable toxicity in relapsed TCL, NHL, B cell lymphoma, an untreated or relapsed CLL, both as monotherapy and in combination with other anti-cancer agents [82][83][84], suggesting that it could be used in standard of care regimens for treating these disorders.
Deubiquitinating enzymes (DUBs) Inhibitors. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins [85]. Ubiquitylation processes control several physiological programs, and their deregulation contributes to the pathogenesis of many diseases [85]. For these reasons, DUB inhibitors have been investigated as potential anti-cancer agents in preclinical studies, although to date, none of them has reached clinical trials. In the last few years, using in silico assays, several potent and selective allosteric USP7 inhibitors have been identified (i.e., P50429, GNE-6640 and GNE-6776) [86]. Recently, a novel proteasome deubiquitinase inhibitor, VLX1570, was demonstrated to bind to and inhibit the activity of Ubiquitine Specific Proteases 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5) in vitro. Moreover, VLX1570 treatment was shown to promote MM apoptosis and reduce MM growth in vivo. Although VLX1570 also showed anti-tumor effects in patients with relapsed and refractory MM, the phase I study was discontinued due to severe lung toxicity [87].

2.3. NF-κB Transcription Factors

Selectively targeting NF-κB at the transcription factor level represents an attractive therapeutic strategy for the treatment of human hematological diseases. IT-901 is a novel inhibitor of the c-Rel and p65 NF-κB subunits. Treatment with IT-901 was shown to reduce lymphoma cell survival both in vitro and in vivo by blocking NF-κB-mediated oxidative stress response [88][89]. Accordingly, human primary CLL and Richter syndrome (RS) cells and CLL cell lines died by apoptosis upon IT-901 treatment, and no apparent toxicity was observed in normal B and T lymphocytes or in stromal cells [90]. IT-901 was also able to reduce tumor growth in vivo. Furthermore, reduced NF-κB binding to its consensus DNA site was observed in CLL cells as a consequence of NF-κB complex degradation in the cytosol. IT-901 induces anti-tumor effects by a dose-dependent increase in mitochondrial reactive oxygen species (ROS) along with a reduction of NF-κB-dependent transcription of genes encoding for Cytochrome c oxidase assembly subunit 2 (SCO2), ATP-synthase, and ATP5A1, as well as ROS scavenger, catalase (CAT), mitochondrial membrane potential, maximal Oxygen Consumption Rate (OCR), and ATP production [90]. The combination of IT-901 with ibrutinib, which is a first line therapy for CLL patients, increased the cytotoxic effect of both drugs, underling their potential use as combination therapy [90]. Collectively, this package of preclinical data showing the cancer-selective mode of action of IT-901 supports the further progression of this drug for clinical development.
Recently, the NF-κB transcription factor-PROTAC (NF-κB-PROTAC) was developed with the aim of selectively degrading p65 protein; it was proven to induce antiproliferative effects in cells, although in vivo studies are needed to validate both its efficacy and safety [64].

2.4. NF-κB Nuclear Activities

The shuttling of NF-κB dimers between cytoplasm and nucleus is critical to promote NF-κB transcriptional programs [91]. The deregulation of this process has been observed in many disease conditions, suggesting that the inhibition of NF-κB nuclear activity (i.e., post-translational modification of NF-κB proteins and their ability to dimerize, translocate into the nucleus, bind to DNA, and interact with chromatin components, coactivators, and corepressors and other transcription factors) could be a potential therapeutic approach.
Inhibitors of nuclear translocation. NF-κB nuclear translocation is a highly controlled process which is involved different signals, i.e., nuclear localization signals (NLS), leucine-rich nuclear export signals (NES)), receptors (chromosome region maintenance 1/exportin1/Exp1/Xpo1 (CRM1)) and nuclear pore complexes (NPCs) [92][93]. Nuclear translocation of NF-κB is mediated by the NLS. After IκBα poly-ubiquitination and proteasomal degradation, NF-κB dimers interact with importin α/β and are carried into the nucleus through NPCs. 
Although NF-κB nuclear import inhibitors have not entered clinical trials yet, many of them have been tested for their ability to inhibit NF-κB nuclear translocation, including synthetic small peptidomimetics SN-50, anti-inflammatory peptide-6 (AIP6), Ivermectin, Importazole, and dehydroxymethylepoxyquinomicin (DHMEQ) [94][95][96][97][98][99]. While Ivermectin and Importazole are importin α/β inhibitors, SN-50 blocks NF-κB nuclear import by inhibiting the NLS on the NF-κB complex [94][95][96][97]. AIP6 was demonstrated to directly interact with p65 and block the DNA-binding and transcriptional activities of the p65 NF-κB subunit in vitro. In addition, AIP6 displayed significant anti-inflammatory properties both in vitro and in vivo [98]. It has been demonstrated that DHMEQ promotes tumor regression and anti-inflammatory response in many cancer types including breast and ovarian and cisplatin-resistant NSCLC cancers, both in cell lines and xenograft mouse models [100][101][102][103]. DHMEQ exerts its anti-NF-κB activity by directly binding to NF-κB subunits (i.e., RelA, c-Rel or RelB) and blocking their nuclear translocation [99]. DHMEQ-mediated NF-κB inhibition was shown to induce downregulation of NF-κB-dependent anti-apoptotic genes and CLL cell death in vitro [100].
Inhibitors of NF-κB transcriptional activity. NF-κB transcriptional activity is also regulated by post-translational modifications such as ubiquitination, acetylation, methylation, SUMOylation, and phosphorylation [104][105]. Acetylation and deacetylation of NF-κB are under the control of histone acetyltransferase (HATs) and histone deacetylase (HDACs), respectively, and different coactivators (i.e., p300, CREB binding protein (CBP), HIV Tat-interacting protein 60 (Tip60)) [106].
Inhibitors of NF-κB transactivation and DNA binding. Another way to inhibit the NF-κB pathway is to target NF-κB transactivation, its binding to DNA, as well as the coactivators and corepressors involved in NF-κB-mediated transcription. Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extra-terminal domain (BET) protein family, which is involved in the control of transcriptional machinery via binding to acetylated lysine residues of proteins, including NF-κB, [107][108]. OTX015 is the most characterized BET inhibitor. It is capable of disrupting the interaction between BET proteins and NF-κB dimers at promoters and has shown clinical efficacy in patients with refractory or relapsed hematological cancers [109][110]. Other BET inhibitors (i.e., cPI-0610, ZEN003694, BMS-986158) are being tested in several clinical trials for hematological and solid cancer, both as standalone treatments and in combination with other anti-cancer agents (NCT04986423; NCT05391022; NCT02158858; NCT03936465). A phase I study of GSK525762 (molibresib), a bromodomain and extra-terminal domain inhibitor, showed clinical benefit and acceptable adverse effects in patient with solid tumors, suggesting that this inhibitor could be a promising therapeutic agent [111].
NF-κB DNA binding inhibitors such as parthenolide (PN, a sesquiterpene lactone (SL)) and dimethylaminoparthenolide (DMAPT) are potent anti-inflammatory compounds which are able to covalently bind to the cysteine-38 residue of the p65 NF-κB subunit and inhibit p65 DNA binding, thus deregulating NF-κB activation [112]. To date, several preclinical studies of parthenolide in combination with other drugs such as DMAPT, HDAC inhibitors, and anthracyclines have been conducted; they showed that PN increases cancer cell apoptosis and reduces drug resistance, despite the poor bioavailability of this compound [113][114]. Conversely, DMAPT has a better bioavailability than PN; it showed anti-tumor activity both in vitro and in vivo in many cancer types and is thus considered promising for clinical translation [115][116][117].
Targeted drug delivery to tumor sites could be a potential new strategy to ameliorate internalization and avoid off-target toxicity. Emerging evidence showed that the use of aptamers, proteins, and antibodies conjugated to anti-tumor drugs and specifically targeting with high affinity molecules which are overexpressed in cancer cells is an active area of interest [118]. Recently, synthetic double-stranded oligonucleotides (ODNs) targeting NF-κB transcription factor, also known as NF-κB decoy ODNs, were conjugated to the RNA aptamer against transferrin receptor (TfR) and Doxorubicin (Dox) to generate an ODN chimera, named aptacoy. Aptocoy is able to selectively target pancreatic tumor cells by recognizing TfR—which is overexpressed in pancreatic cancer—and releasing Doxorubicin along with NF-κB decoy ODNs to sensitize tumor cells to Dox-induced cell death [119]. Accordingly, pancreatic cancer cells treated with aptacoy showed a reduction of NF-κB target gene expression and increased apoptosis in vitro [119]. Despite promising preclinical data, aptacoy has not entered clinical trials yet due to its poor uptake into cells, and further investigations are needed to optimize the physicochemical and pharmacological properties of these molecules.
Despite the clinical improvements observed following treatment with core pathway inhibitors in specific tumors, concerning proteasome inhibitors in MM, these anti-cancer drugs target the NF-κB pathway in both cancer and normal cells, often resulting in severe toxic effects at effective dose levels. In addition, drug resistance remains a major obstacle to the successful treatment of cancer, suggesting that further investigations are needed to overcome these limitations. In this regard, new drug candidates have progressed to phase III trials and seem to be well tolerated (i.e., Icaritin and MLN4924), while others (i.e., IT-901) showed cancer-selectivity in preclinical studies. Furthermore, novel therapeutic tools like PROTACs, which provide a platform to achieve selective degradation of specific NF-κB pathway components, are being tested in vitro. While these new therapeutics hold promise, they need to be clinically validated, underscoring that the development of disease-specific, clinically useful anti-NF-κB agents is still an unmet medical need.

3. Inhibitors of NF-κB Downstream Effectors

The barrier to therapeutically targeting NF-κB has been achieving disease-cell specificity, given the ubiquitous functions of NF-κB. Since NF-κB drives pathology by inducing tissue- and context-specific transcriptional programs, several research groups have pursued an alternative approach to overcome this barrier, i.e., targeting essential, specific effectors of NF-κB pathogenetic functions, including the promotion of cell survival, angiogenesis, inflammation, and metabolic adaptation, which are fundamental processes in a range of human disorders, including cancer [120][121].
The principal effectors of NF-κB pro-angiogenetic function belong to the vascular endothelial growth factor (VEGF) family, which comprises five members: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PIGF). These factors interact with several tyrosine-kinase receptors such as VEGFR-1, VEGFR-2, and VEGFR-3 to promote tumor-associated angiogenesis, tissue infiltration, and metastasis formation [122][123]. Bevacizumab (BVZ) is a humanized anti-VEGF-A monoclonal antibody which is able to block the interaction between VEGF-A and its receptor by binding circulating and soluble VEGF-A [123]. BVZ is the first anti-angiogenic drug approved by FDA and EMEA for the treatment, in combination with chemotherapy, of metastatic CRC, OC, breast, renal, and NSCLC cancers, and as monotherapy for the treatment of GBM. The combination of BVZ with immune checkpoint inhibitors is currently under clinical investigation and could represent a promising treatment option for patients with unresectable HCC or untreated metastatic renal cell carcinoma (mRCC) (NCT03434379; NCT02715531; NCT02420821) [124][125]. Along with BVZ, Aflibercept was approved by the FDA in combination with chemotherapy for the treatment of metastatic CRC [69]. Moreover, the VEGFR-1 inhibitor, Sunitinib, has also been approved by FDA for the treatment of renal cell cancer, gastrointestinal stromal tumors (GISTs), and progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) [69][126].
The role of NF-κB in mediating tumor-promoting inflammation has been widely recognized [38]. Proinflammatory cytokine interleukin-6 (IL-6) is one of the key proinflammatory genes induced by NF-κB; its role in tumorigenesis and inflammatory diseases has been extensively elucidated. Effective anti-IL-6 agents have been developed and, to date, the monoclonal antibodies (mAb) tocilizumab (anti-IL-6R) and siltuximab (anti-IL-6) are approved by the FDA for the treatment of RA and Castleman’s disease, respectively [127]. The use of IL-6 blockers as anti-cancer agents has been evaluated in many cancers (i.e., lung, prostate cancers, OC, B-cell NHLS, renal cell carcinoma) [127]. Although Elsilimomab (BE-8) did not show clinical efficacy in cancer patients, other anti-IL-6 mAbs such as mAb 1339 (OP-R003) and ALD518/BMS-945429 have exhibited potential anti-tumor activity in vivo, inducing significant clinical response in patients with different disorders [127], suggesting that they could be used to treat cancer. Furthermore, the anti-IL-6 mAb, siltuximab, is being tested in clinical trials for several cancers such as large granular lymphocytic leukemia (LGLL), metastatic pancreatin cancer, and MM, both alone and in combination therapy (NCT05316116; NCT04191421; NCT03315026). Recently, Hailemichael and collaborators showed that IL-6R blockade abrogates immunotherapy-associated toxicity, thus reinforcing anti-tumor immunity in vivo [128]. Accordingly, the combination therapy of tocilizumab and immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) is currently in phase II trial for patients with melanoma, NSCLC, and urothelial carcinoma (NCT04940299) [129][130].
Recently, CES1 has been identified as an essential NF-κB-regulated lipase linking obesity-associated inflammation with metabolic adaptation to energy stress in aggressive CRC [131][132][133]. CES1 expression was upregulated in consensus molecular subtypes (CMS)4 and CMS2 tumors and correlated with worse clinical outcomes in overweight CRC patients [131][132][133], suggesting a role for CES1 in the pathogenesis of CRC. Consistent with this idea, treatment with CES1 inhibitors effectively killed human CRC cells upon glucose limitation and markedly impaired CRC growth without apparent adverse effects in mouse allograft and xenograft models [131][132][133]. Collectively, these results identify CES1 as a promising therapeutic target, given its contextual specificity for energy stress conditions, correlation with poor clinical outcomes in obese CRC patients, and clear stratification with MSS/non-hypermutated CMS4 and CMS2 tumors, which do not respond to immunotherapy [131][132][133]. Accordingly, genetic CES1 deletion appears to be tolerated in vivo, since CES1 knockout mice are viable, lean, and die of old age [134].
Collectively, this bulk of evidence demonstrates that the safe and cancer-selective inhibition of the NF-κB pathway is clinically achievable and promises profound benefit to patients with NF-κB-driven cancers.

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