Radio- and Chemosensitization of Human Papillomavirus (HPV)-Negative Head and Neck Squamous Cell Carcinomas by the SMAC Mimetic LCL161
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Date
2017-05
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The Ohio State University
Abstract
The 6th most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) has a 5-year survival rate of only 40-50%. Furthermore, HNSCC is differentiated between human papillomavirus (HPV) positive and negative types, the latter of which is correlated with worse clinical outcomes. Thus, there is a need for novel therapies to improve outcomes in this disease. One potential novel treatment is LCL161 in combination with radiation (RT) and chemotherapy (e.g. cisplatin, paclitaxel, Abraxane, gemcitabine). LCL161 is part of a new class of targeted drugs, second mitochondria-derived activator of caspase (SMAC) mimetics, that can induce apoptotic cell death by antagonizing inhibitors of apoptosis family proteins (IAPs). The purpose of this study is to investigate the ability of LCL161 to radio- and chemosensitize HPV- HNSCCs in vitro and to validate our findings in vivo. To test the radiosensitizing effect of LCL161 in vitro, we first examined TCGA data and conducted Western blots on HPV- and HPV + HSNCC cell lines to measure levels of IAPs. Additionally, tissue microarrays (TMAs) were used to evaluate the expression of cIAP1 and its correlation with HPV status and patient survival. We hypothesized that a higher expression of IAPs will correlate with an increased radio- and chemosensitization effect by LCL161. Clonogenic assays were then utilized to determine radio- and chemosensitization via LCL161. Cell cycle analysis, Annexin-V staining, and immunoblotting were used to determine the mechanism of LCL161-induced radiosensitization. Lastly, human xenografts were used to validate the radiosensitizing effect of LCL161 on HPV- HNSCC tumors in vivo. We discovered that cIAP1 expression was higher in HPV- HNSCC cells and cIAP1 expression was associated with poorer overall survival. These HPV(-) cells were radiosensitized by LCL161 with drug enhancement ratios of 1.21 and 1.23 for Cal27 and UM-SCC-1, respectively. Conversely, HPV(+) cell lines were not significantly radiosensitized after treatment with LCL161. Furthermore, we found that LCL161-mediatted radiation was attributable to enhanced radiation induced apoptosis. The addition of various chemotherapies also chemosensitized the HPV(-) cells, enhancing the results of LCL161 combined with RT. Finally, we confirmed the ability of LCL161 to radiosensitize HNSCC tumors in vivo with human cell line xenograft mouse models.
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Keywords
Head and Neck Squamous Cell Carcinoma, LCL161, Smac Mimetic, Cancer