Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity

Abstract

Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health, including chronic inflammatory diseases, autoimmune disorders, diabetes, vascular diseases and the majority of cancers. Accordingly, the NF-κB pathway is widely considered an attractive therapeutic target in a broad range of malignant and non-malignant diseases. Yet, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB. In this review, we summarise the main strategies historically adopted to therapeutically target the NF-κB pathway with an emphasis on oncology, and some of the emerging strategies and newer agents being developed to pharmacologically inhibit this pathway.

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

“…As the IKK complex plays a crucial role in signal integration for NF-κB activation pathways, it has attracted much interest and research into compounds that are able to block IκB phosphorylation and, hence, also prevent ubiquitination of IκBα and its further degradation [ 25 , 140 , 141 ]. However, while many inhibitors have been developed, few have managed to enter into clinical trials and none have been clinically approved [ 141 , 142 ]. However, it must also be noted that while the targeting IKK2 holds promise as a likely anti-inflammatory therapy, it was found that pharmacological IKK2 inhibition can also result in increased endotoxin susceptibility that is associated with increased levels of IL-1β as a result of increased pro-IL-1β secretion by macrophages and neutrophils upon bacterial infections, thereby causing overt systemic inflammation and lethality in mice [ 143 ].…”

Post-translational Modifications of IκBα: The State of the Art

“…It should be emphasized that in addition to the NF-κB pathway, proteasome inhibitors regulate many other important cellular pathways that depend on proteasome function and affect these signal transduction pathways in both normal and cancer cells, resulting in some limitations to their clinical use, including dose-limiting side effects and the rapid onset of secondary drug resistance (Begalli et al, 2017). For example, bortezomib usually causes peripheral neuropathy, whereas carfilzomib can cause cardiotoxicity, acute renal failure, pulmonary toxicity and other adverse reactions (Narayanan et al, 2020).…”

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

“…However, the potential risks of on-target systemic toxicity, immunodeficiency and malignant development arising in contexts where IKKβ/NF-κB activity plays a dominant tumour suppressor role may prove insurmountable and forever undermine research efforts to clinically develop IKKβ-targeting therapeutics. Some, if not all, of these safety concerns may be circumvented by targeting alternative nodes in the NF-κB pathway [ 226 , 227 ]. Indeed, this strategy has seen far greater clinical success than directly targeting IKKβ.…”