Targeting inhibitor of apoptosis proteins for cancer therapy: a double-edge sword?

Evasion of programmed cell death is a hallmark of human cancers. Inhibitor of apoptosis (IAP) proteins such as X-chromosome– linked IAP (XIAP) and cellular IAP (cIAP) proteins play an important role in supporting cell survival by blocking cell death. IAP proteins comprise at least one of the signature baculoviral IAP repeat domains, a protein-protein motif critical for their binding to and inhibition of caspases to block the implementation of cell death. Some IAP proteins also contain the really interesting new gene domain with E3 ubiquitin ligase activity responsible for ubiquitination, leading to proteasomal degradation or altered signaling functions of substrates. Because IAP proteins are expressed at high levels in human cancers and contribute to tumor progression, treatment resistance, and poor prognosis, they have attracted considerable attention as therapeutic targets for drug development. To this end, smallmolecule inhibitors have been developed that mimic the N-terminal portion of second mitochondria-derived activator of caspases (Smac), an endogenous IAP antagonist that is released from mitochondria into the cytosol during apoptosis. IAP inhibitors, also called Smac mimetics, are composed of one (monovalent) or two (bivalent) Smac-mimicking units. Smac mimetics induce apoptosis in cancer cells by binding to and neutralizing XIAP, thereby releasing caspases from the inhibitory functions of XIAP (Fig 1). In addition, the binding of Smac mimetics to cIAP proteins stimulates the E3 ligase activity of cIAP1 and cIAP2, leading to their autoubiquitination and degradation via the proteasome (Fig 1). Because cIAP proteins constitutively mediate ubiquitination and degradation of nuclear factor kappa B (NFB) –inducing kinase, a key component of the noncanonical NFB pathway, the Smac mimetic–mediated depletion of cIAP proteins results in accumulation of NFB–inducing kinase, activation of the noncanonical NFB pathway, and upregulation of NFB target genes, including inflammatory cytokines such as tumor necrosis factor (TNF ). TNF , a member of the death receptor ligand family, then triggers cell death on binding to its cognate cell surface receptor TNF receptor 1 in an autocrine/paracrine manner. The concomitant Smac mimetic– triggered loss of cIAP proteins is critical for TNF -induced cell death by shutting off ubiquitination of receptor-interacting protein 1, thereby promoting its interaction with Fas-associated protein with death domain and caspase-8 to form a cytosolic cell death complex that drives caspase-8 activation and apoptosis. Smac mimetics have repeatedly been shown to either directly induce apoptosis or to sensitize cancer cells for apoptosis in response to additional cytotoxic treatments. More than a decade ago, a proof-of-concept study used a preclinical in vivo cancer model to demonstrate the feasibility of targeting IAP proteins by Smac mimetics for cancer therapy. Currently, five distinct Smac mimetic compounds have been evaluated in early clinical trials, including LCL161, a monovalent, orally bioavailable drug. The article by Infante et al that accompanies this Understanding the Pathway reports on the first-inhuman, phase I dose-escalation study of LCL161 in patients with advanced solid tumors. Objectives of the study were to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), TNFα