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HNSCC with Casp8 Loss is Sensitized to Necroptosis

Head and Neck Squamous Carcinoma (HNSCC) is one of the most common cancers in the world, due to its rigid resistance to standard-of-care therapy, the 5-year survival rate for HNSCC remains as low as 50%. According to integrative genomic analysis of HNSCC, caspase8 (Casp8) is one of the most frequently mutated genes, which enhances the survival of cancer cells because they are less susceptible to Casp8-mediated apoptosis induced by cytokines or radiation. To overcome apoptotic resistance and explore other effective cancer therapeutics, necroptosis, another programmed cell death that is usually inhibited by Casp8, has attracted extensive attention in recent years. 

Burak Uzunparmak et al. found that HNSCC cell lines with known Casp8 mutants are significantly more radioresistant. To understand whether necroptosis can be exploited to re-sensitize Casp8-deficient HNSCC cells to radiation, they manually knocked down the Casp8 in HNSCC cells and induced necroptosis by subjecting the cells to different combinations of chemicals. Just as they expected, the HNSCC cells became sensitive to radiation again when necroptosis was induced (Figure1). They also constructed in vivo Casp8-deficient mouse model to test their hypothesis further. After treating the mice with necroptosis induction agents and exposing them to radiation, the tumor growth in mice was delayed and accompanied survival benefits were observed (Figure1).

Figure1. HNSCC cells/In vivo xenograft mice with Casp8 loss are sensitized to radiation when necroptosis is induced

One potential concern in this study is the expression level of RIPK3 in cancer cells. RIPK3 is known to play a pivotal role in determining the sensitivity of the cancer cells to necroptosis. However, many HNSCC cell lines lack functional RIPK3 protein and exhibit necroptosis resistance. Burak Uzunparmak et al. tested the expression levels of “executioner” proteins involved in the necroptotic pathway. The results showed that only 3 out of 9 HNSCC cell lines demonstrated considerable baseline protein levels of RIPK3. Therefore, to validate the potential application of necroptosis as a therapeutic target in HNSCCs, they assessed RIP3 gene expression in HNSCC tumors using The Cancer Genome Atlas (TCGA) HNSCC dataset, which is publicly available. The analysis of TCGA tumors confirmed the high levels of RIPK3 in most tumors, providing the opportunity for the therapeutic use of necroptosis in HNSCC. 

One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Evasion of apoptosis contributes to carcinogenesis, tumor progression and the resistance to anticancer treatments, including chemotherapy, radio- and immunotherapy primarily act by activating cell death pathways. As the research on biochemical apoptotic pathways developed, the “cross-talk” between apoptotic and necroptotic cell death has been revealed, leading to the focus on necroptosis when apoptosis becomes resistant. Burak Uzunparmak et al.  provides a piece of evidence illustrating that although the mutated Caps8 in HNSCCs causes resistance to apoptosis, it at the same time makes it possible to activate necroptosis as an alternative pathway to treat cancers. 

Reference:
Burak Uzunparmak., et al. Loss of Caspase-8 function in combination with SMAC mimetic treatment sensitizes Head and Neck Squamous Carcinoma to radiation through induction of necroptosis. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.17.039040. 

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