A review on the role of TANK-binding kinase 1 signaling in cancer

Abstract

TANK-binding kinase 1 (TBK1) regulates various biological processes including, NF-κB signaling, immune response, autophagy, cell division, Ras-mediated oncogenesis, and AKT pro-survival signaling. Enhanced TBK1 activity is associated with autoimmune diseases and cancer, suggesting its role in therapeutic targeting of interferonopathies. In addition, dysregulation of TBK1 activity promotes several inflammatory disorders and oncogenesis. Structural and biochemical study reports provide the molecular process of TBK1 activation and recap the substrate selection about TBK1. This review summarizes recent findings on the molecular mechanisms by which TBK1 is involved in cancer signaling. The IKK-ε and TBK1 are together associated with inflammatory diseases by inducing type I IFNs. Furthermore, TBK1 signaling regulates radiation-induced epithelial-mesenchymal transition by controlling phosphorylation of GSK-3β and expression of Zinc finger E-box-binding homeobox 1, suggesting, TBK1 could be targeted for radiotherapy-induced metastasis therapy. Despite a considerable increase in the list of TBK1 inhibitors, only a few has potential to control cancer. Among them, a compound BX795 is considered a potent and selective inhibitor of TBK1. We discussed the therapeutic potential of small-molecule inhibitors of TBK1, particularly those with high selectivity, which will enable further exploration in the therapeutic management of cancer and inflammatory diseases.

Keywords: Autophagy; Cell division; Immune infiltration; Inflammation; Kinase inhibitors; Signaling; TANK-binding kinase 1; Targeted therapy.