Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic–induced necroptosis

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.

Caspase‐8: A key protein of cross‐talk signal way in “PANoptosis” in cancer

“…Does an in‐depth study of the connection between caspase‐8 and precancerous lesions help to inhibit the occurrence of cancer? Interestingly, in head and neck squamous cell carcinoma (HNSCC), the inhibition of caspase‐8 and the second mitochondria‐derived activator of caspases (SMAC) derived from the mitochondria can induce necroptosis to enhance the radiosensitization effect on HNSCC 77 . Fianco et al 61 found that caspase‐8 could maintain tumor transformation in human glioblastoma multiforme (GBM) in vitro.…”

Death agonist antibody against TRAILR2/DR5/TNFRSF10B enhances birinapant anti-tumor activity in HPV-positive head and neck squamous cell carcinomas

“…We next examined the genetic alterations of TP53 and CASP8 , which are important molecules that modulate the cell apoptosis pathway 5 , 24 , 25 . The genetic alterations of TP53 and CASP8 from HNSCC TCGA datasets were displayed by Oncoprint, which showed 71% TP53 and 13% CASP8 mutation rates, mainly in HPV(−) HNSCC (Supplemental Figure 2 A).…”

“…In addition, we investigated the genetic alteration rates of TP53 and CASP8 , which are known to play important roles in cell apoptosis in the updated HNSCC TCGA cohort 5 , 24 , 25 . We observed the differential genetic alterations of TP53 and CASP8 between HPV(−) versus HPV(+) HNSCC (Supplemental Figure 2 A).…”

“…In HPV(−) HNSCC, we observed high rates of deleterious mutations of TP53 and CASP8, that are critical in apoptosis and are the pathogenesis and resistance to therapies. The Pickering group showed that CASP8 is mutated in a subset of HPV(−) HNSCC 24 . TP53 is also mutated mainly in HPV(−) HNSCC, but with a much lower rate in HPV(+) cancers, where the TP53 protein is inactivated instead by HPV E6 oncoprotein through constant binding and degradation of TP53 protein 32 .…”

Prognostic Genetic Biomarkers Based on Oncogenic Signaling Pathways for Outcome Prediction in Patients with Oral Cavity Squamous Cell Carcinoma

“…Oncogenic HRAS sensitized fibroblasts to TRAIL-induced apoptosis. In addition, CASP8 cleavage and CASP8, which were also found frequently (11.2%) in head and neck squamous cell carcinomas [ 10 ], are associated with poor overall survival in univariate and multivariate analyses [ 28 ].…”