Abstract 137: Targeting IAPs: NF-κB signaling pathways play a critical role in IAP antagonist induced apoptosis

Abstract

Abstract Inhibition of apoptosis enhances the survival of cancer cells and facilitates their escape from immune surveillance and cytotoxic therapies. Inhibitor of apoptosis (IAP) proteins are anti-apoptotic regulators that block cell death in response to diverse stimuli. Because these proteins play an active role in promoting tumor maintenance, they are attractive targets for developing a novel class of cancer therapeutics. Through TRAF2 interactions, c-IAP1 and c-IAP2 are recruited to tumor necrosis factor receptor 1 (TNFR1)-associated protein complexes where they regulate receptor-mediated signaling. The ubiquitin E3 ligase activity of c-IAP1/2 regulates canonical and noncanonical NF-κB pathways by promoting ubiquitination of RIP1 and NIK. We have designed small-molecule IAP antagonists that bind with high affinities to select baculovirus IAP repeat (BIR) domains of IAPs resulting in a dramatic induction of c-IAP auto-ubiquitination and rapid proteasomal degradation. Neutralization of c-IAPs through knockdown or small-molecule IAP antagonists blunts TNF stimulated NF-κB activation and greatly sensitizes cells to TNF induced cell death. Investigation of death receptor signaling complexes revealed that FLIP plays an important role in IAP antagonist stimulated apoptotic pathways and that down-regulation of FLIP sensitizes otherwise resistant cells to IAP antagonist induced cell death. In addition, regulation of NF-kB signaling pathways by cellular IAPs represents a pivotal point in IAP antagonists induced cell death. The interplay between pro-survival and pro-apoptotic signaling involves multiple levels of coordination and the regulation of these processes can determine the fate of treated cells. Finally, our IAP antagonists inhibit tumor growth in vivo as single agents and in combination with a number of standard of care anti-tumor agents including death receptor agonists. Interestingly, while single-agent activity of IAP antagonists relies on TNF signaling, the synergistic activity of IAP antagonists with FasL or anti-DR5 antibody does not depend on TNF signaling but on XIAP antagonism. Understanding the significance of protein stability and death receptors mediated pathways for inhibition of apoptosis by IAP proteins is important for the design of potent IAP-directed compounds. These compounds can be used in the treatment of malignancies in which IAP expression contributes to tumor progression and resistance to conventional chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 137.