NFκB signalling in colorectal cancer: Examining the central dogma of IKKα and IKKβ signalling.

The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.