Abstract
One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.
Highlights
One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis
The inhibitor of apoptosis (IAP) proteins are a family of endogenous proteins that function as key regulators of caspase activity, and are defined by the presence of at least one Baculoviral inhibitor of apoptosis proteins (IAPs) Repeat (BIR) domain
Single agent efficacy of SMs has been reported, for the treatment of certain leukaemias [51,52,53]. These monotherapy studies have shown that, for the most part, antagonism of IAPs alone does not result in immediate cell death; rather, SM-induced assembly of the ripoptosome can prime cells for death—a process which requires an additional RIPK1 activating signal [1,30,31], which lowers the threshold for TNF-dependent apoptotic cell death
Summary
The capacity to evade apoptosis, a form of physiological cell death that relies on the activation of a family of cysteine proteases known as caspases [1], is a common trait of malignantly transformed cells [2]. The inhibitor of apoptosis (IAP) proteins are a family of endogenous proteins that function as key regulators of caspase activity, and are defined by the presence of at least one Baculoviral IAP Repeat (BIR) domain. IAPs contain a RING finger E3 ligase domain at the C-terminus [8,9], enabling these proteins to participate in diverse cellular processes, including signal transduction events that promote inflammation, cell cycle progression and migration.
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