Abstract
Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCCs), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCCs suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, birinapant, in combination with pan-caspase inhibitors Z-VAD-FMK or emricasan and radiation. In a syngeneic mouse model of oral cancer, birinapant, particularly when combined with radiation, delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels rendered many HNSCC cell lines resistant to necroptosis, patient tumors maintained RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.
Highlights
Head and neck squamous carcinoma (HNSCC), which comprises epithelial tumors originating from the mucosa of oral cavity, oropharynx, larynx, and hypopharynx, is one of the most common cancers in the world, with the diagnosis of nearly 650,000 new cases and more than 300,000 cancer-related deaths annually [1]
We found that deletion of CASP8 rendered HNSCCs susceptible to necroptosis induced by the second mitochondria-derived activator of caspase (SMAC) mimetic birinapant
To determine whether poor overall survival outcomes might be linked to radioresistance in CASP8-mutant HNSCCs, we selected a panel of 46 HNSCC cell lines with known CASP8 status [28]
Summary
Head and neck squamous carcinoma (HNSCC), which comprises epithelial tumors originating from the mucosa of oral cavity, oropharynx, larynx, and hypopharynx, is one of the most common cancers in the world, with the diagnosis of nearly 650,000 new cases and more than 300,000 cancer-related deaths annually [1]. Integrative genomic analysis of HNSCC has uncovered that caspase-8 (CASP8) is one of the most frequently mutated genes in HNSCC, with somatic mutations detected in approximately 10% of cases [3, 4]. CASP8 is an aspartate-specific cysteine protease that plays a key role in the initiation of extrinsic apoptosis [5]. Because of the key role it plays in death receptor–mediated apoptosis, CASP8 has long been considered a tumor suppressor gene [9].
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