NF-κB in the crosshairs: Rethinking an old riddle

• Published in: The international journal of biochemistry & cell biology Vol. 95; pp. 108 - 112
• Main Authors: Bennett, Jason, Capece, Daria, Begalli, Federica, Verzella, Daniela, D’Andrea, Daniel, Tornatore, Laura, Franzoso, Guido
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-02-2018; Elsevier
• Subjects: Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cancer; Cell Survival - drug effects; Drug Design; Drugs, Investigational - adverse effects; Drugs, Investigational - chemistry; Drugs, Investigational - pharmacology; Drugs, Investigational - therapeutic use; DTP3; GADD45β; Humans; IKKβ; Models, Biological; Molecular Targeted Therapy - adverse effects; Molecular Targeted Therapy - trends; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; Signal Transduction - drug effects; CLL; DLBCL; FDA; B; cFLIP; DIABLO; RAS; JNK; PTEN; XIAP; IKKβ; BCL-2; NF-κB; GBM; DTP3; GADD45β; SMAC; cIAP; FLICE; MCL1; BCL-XL; IKK; IL-1β; TME; βTrCPP; BFL-1; IκBα; SCF; MAP; MALT; Cancer
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2017.12.020

•NF-κB transcription factors are central coordinating regulators of immunity, inflammation and cell survival.•NF-κB pathway is aberrantly and stably activated in cancer.•The ubiquitous presence and pleiotropic physiological role of NF-κB dimers have thus far prevented the development of any clinically useful NF-κB inhibitor.•Emerging therapeutic approaches aim to achieve the cancer-selective inhibition of the NF-κB pathway as a way to overcome the preclusive toxicities of conventional IKKβ/NF-κB-targeting drugs.
Constitutive NF-κB signalling has been implicated in the pathogenesis of most human malignancies and virtually all non-malignant pathologies. Accordingly, the NF-κB pathway has been aggressively pursued as an attractive therapeutic target for drug discovery. However, the severe on-target toxicities associated with systemic NF-κB inhibition have thus far precluded the development of a clinically useful, NF-κB-targeting medicine as a way to treat patients with either oncological or non-oncological diseases. This minireview discusses some of the more promising approaches currently being developed to circumvent the preclusive safety liabilities of global NF-κB blockade by selectively targeting pathogenic NF-κB signalling in cancer, while preserving the multiple physiological functions of NF-κB in host defence responses and tissue homeostasis.