Thereare only few agents that are truly cancer cell-specific. Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a potent death inducing cytokine and a rare example of such molecules that kill transformed cells but spare normal ones. Activating the “extrinsic” apoptotic pathway, selectively in cancer cells, both with the recombinant human ligand (rhTRAIL) or agonistic antibodies (Mapatumumab, Apomab) has therefore been a goal of cancer researchers and pharmaceutical companies for many years.
TRAIL receptor agonists, however, have performed poorly in the clinic due to major gaps in our understanding of what drives resistance to these potent death inducers. Several factors can contribute to the non-sensitivity of cancer cells upon TRAIL-stimulation, including elevated levels of negative regulators of apoptosis.
We have identified two new molecules, a RING-type ubiquitin E3 ligase Mind Bomb-2 (MIB2) and MIB2 interacting protein (MIP) that inhibit death receptor (DR) signaling and promote tumour development. For the first time we identified MIP as a novel MIB2 interacting protein and demonstrated that theremoval of either MIB2 or MIP reduced tumour development in models for colorectal cancerand was sufficient to sensitize tumour cells to TRAIL-induced cell death.
We also showed that MIB2 can ubiquitylate RIPK1 andMIP. While it had been demonstrated that MIB2 ubiquitylated RIPK1 to limit TNF-induced cell death, the biological requirement for the ubiquitylation of MIP is still unclear and remains to be determined which ubiquitin linkage-type is attached. Further studies will also be conducted to confirm whether MIB2 can modulate the activities of RIPK1 or MIP in TRAIL signaling.
Furthermore, we assess the therapeutic potential of targeting these molecules for cancer treatment in combination with TRAIL and provide proof of principle evidence that targeting these molecules can have clinical utility. Using Proteolysis targeting chimera (PROTAC) approach we show that MIP and MIB2 can be degraded using available PROTAC drugs.