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

Autor:	An Y; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Jeon J; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA.; NIH Medical Research Scholars Program, Bethesda, MD, USA., Sun L; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Derakhshan A; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Chen J; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Carlson S; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Cheng H; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Silvin C; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Yang X; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA., Van Waes C; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA. vanwaesc@nidcd.nih.gov., Chen Z; Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 10, 7N240, Bethesda, MD, 201892, USA. chenz@nidcd.nih.gov.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2021 Mar 18; Vol. 11 (1), pp. 6392. Date of Electronic Publication: 2021 Mar 18.
DOI:	10.1038/s41598-021-85589-5
Abstrakt:	Head and neck squamous cell carcinomas (HNSCC) induced by human papillomavirus (HPV) have increased recently in the US. However, the distinct alterations of molecules involved in the death pathways and drug effects targeting inhibitor of apoptosis proteins (IAPs) have not been extensively characterized in HPV(+) HNSCC cells. In this study, we observed the distinct genomic and expression alterations of nine genes involved in cell death in 55% HNSCC tissues, which were associated with HPV status, tumor staging, and anatomic locations. Expression of four genes was statistically correlated with copy number variation. A panel of HPV(+) HNSCC lines showed abundant TRAILR2 and IAP1 protein expression, but were not sensitive to IAP inhibitor birinapant alone, while combinatory treatment with TNFα or especially TRAIL enhanced this drug sensitivity. The death agonistic TRAILR2 antibody alone showed no cell inhibitory effects, whereas its combination with birinapant and/or TRAIL protein demonstrated additive or synergistic effects. We observed predominantly late apoptosis mode of cell death after combinatorial treatments, and pan-caspase (ZVAD) and caspase-8 (ZIETD) inhibitors attenuated treatment-induced cell death. Our genomic and expression data-driven study provides a framework for identifying relevant combinatorial therapies targeting death pathways in HPV(+) HNSCC and other squamous cancer types.
Databáze:	MEDLINE
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