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Supplementary Table 1 and Supplementary Figures 1-7 from LCL161, a SMAC-mimetic, Preferentially Radiosensitizes Human Papillomavirus–negative Head and Neck Squamous Cell Carcinoma

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posted on 2023-04-03, 15:20 authored by Linlin Yang, Bhavna Kumar, Changxian Shen, Songzhu Zhao, Dukagjin Blakaj, Tianyun Li, Mitchell Romito, Theodoros N. Teknos, Terence M. Williams

Supplementary Table S1. Characteristics of study population (n=84). Supplementary Figure S1. Validation of cIAP1 antibody by immunohistochemistry. Supplementary Figure S2. Sensitivity of HNSCC cells to radiation or LCL161 as a single agent. Supplementary Figure S3. LCL161 does not alter the phosphorylation of STAT3, AKT and ERK in HNSCC cells. Supplementary Figure S4. Altered treatment schedule of LCL161 and radiation does not affect the radiosensitivity of Cal27 cells. Supplementary Figure S5. LCL161 and radiation do not substantially increase tumor cell expression of TNFα(after 24-48 hrs) but does increase TNFα secretion, and TNFα potentiates radiation mediated-apoptosis in tumor cells. Supplementary Figure S6. Kaplan-Meier survival curves demonstrating percent of mice free from tumor doubling are shown for both Cal27 and FaDu xenografts.α

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Ohio State University Comprehensive Cancer Center

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ARTICLE ABSTRACT

Targeting inhibitor of apoptosis proteins (IAP) with second mitochondria-derived activator of caspase (SMAC) mimetics may promote cancer cell death. We tested whether cIAP1 predicts poor prognosis in head and neck squamous cell carcinoma (HNSCC) and whether a novel Smac-mimetic, LCL161, could radiosensitize human papillomavirus–positive (HPV+) and -negative (HPV−) HNSCC. The association of BIRC2 (encoding cIAP1) mRNA level with HPV status in HNSCC was analyzed using The Cancer Genome Atlas (TCGA) database. cIAP1 was assessed by IHC on an HNSCC tissue microarray (TMA, n = 84) followed by correlation analysis with HPV status and patient outcomes. Human cell culture and animal models of HNSCC were used to analyze the outcome and molecular characteristics following radiotherapy in combination with LCL161. cIAP1 expression is increased in HPV− compared with HPV+HNSCC tumors in the TCGA database. In our TMA, cIAP1 was overexpressed in HNSCC compared with normal tissues (P = 0.0003) and associated with a poor overall survival (P = 0.0402). cIAP1 levels were higher in HPV− than that in HPV+HNSCC tumors (P = 0.004) and patients with cIAP1+/HPV− HNSCC had the worst survival. LCL161 effectively radiosensitized HPV− HNSCC cells, which was accompanied with enhanced apoptosis, but not HPV+ HNSCC cells. Importantly, LCL161 in combination with radiotherapy led to dramatic tumor regression of HPV− HNSCC tumor xenografts, accompanied by cIAP1 degradation and apoptosis activation. These results reveal that cIAP1 is a prognostic and a potential therapeutic biomarker for HNSCC, and targeting cIAP1 with LCL161 preferentially radiosensitizes HPV− HNSCC, providing justification for clinical testing of LCL161 in combination with radiation for patients with HPV− HNSCC.