The three major Inhibitor of apoptosis proteins in mammals are XIAP, cIAP1 and cIAP2. Together these three IAPs are pivotal regulators of inflammatory signalling and act to promote inflammatory cytokine production from innate immune signalling receptors such as TNFR1, NOD and TLRs. Surprisingly they also play an opposite role from other inflammatory signalling pathways, inhibiting inflammasome activity and inflammatory cell death. It would be difficult therefore to predict the outcome of inhibiting IAPs in vivo, however the triple XIAP, cIAP1, cIAP2 knock-out mice developed by my lab have a debilitating systemic inflammation. Therefore it would appear that overall IAPs are principally anti-inflammatory.
IAPs may keep cancer cells alive by inhibiting cell death and therefore pharmaceutical companies developed IAP antagonist drugs, called smac-mimetics. Smac-mimetics are very effective antagonists of cIAPs because they promote the auto-ubiquitylation and degradation of cIAPs and directly antagonise XIAP. Smac-mimetics are performing well in clinical trials and well tolerated and surprisingly, given the results from the knock-outs patients, do not appear to promote significant inflammation.
I will describe the phenotype of the triple knock-out mice and discuss how we might incorporate our findings to harness or limit the inflammation promoting potential of smac-mimetics to make them better drugs to treat cancer.