The events downstream of the death receptors can activate inflammatory signalling cascades or drive cell death. Dysregulation of these signalling events is directly linked to one of the key hallmarks of cancer ‘evasion of apoptosis’.
Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a potent death-inducing cytokine widely expressed in normal cells and is of great interest as an anticancer agent since it preferentially initiates apoptosis in tumour cells. However, the clinical response to recombinant TRAIL or TRAIL receptor agonists is unsatisfactory for most cancers, and therapeutics targeting TRAIL death receptors fail to demonstrate long-term significant clinical benefit. To understand the resistance mechanisms, we need to explore other factors that can contribute to a resistant phenotype. These can include, among others, the expression levels of other pro- and anti-apoptotic factors. Ultimately, the molecular understanding of these resistant mechanisms will critically advance the field and lead to improved therapies.
Our work has identified two new proteins: the E3 ubiquitin ligase Mind Bomb-2 (MIB2) and a novel MIB2-interacting protein that block TRAIL-induced death. We reveal that MIB2 is a novel component of native TRAIL complex I, where it contributes to the ubiquitination of the Receptor Interacting Kinase 1 (RIPK1). The removal of either MIB2 or its interacting partner is sufficient to sensitise resistant tumour cells to TRAIL-induced death. Furthermore, we explore the role of these proteins in TRAIL-induced pathology in vivo. Lastly, we employ an innovative proof of principle PROteolysis TArgeting Chimera (PROTAC) approach to trigger the degradation of MIB2 and its interacting protein by directing PROTACs towards small epitope tags (dTAGs). Using dTAG technology we assess the therapeutic potential of targeting these two novel regulators of TRAIL signalling for cancer treatment.