Modulation of death pathways by TRAILR2 agonist antibody in HPV-positive head and neck squamous cell carcinomas

Authors

• Y An
• L Sun
• A Derakhshan
• S Carlson
• R Das
• Z Chen
• C Van Waes

Abstract

Head and neck squamous cell carcinomas (HNSCC) induced by human papilloma virus (HPV(+)) have increased recently in the US, and exhibit a better prognosis and response to therapies than HPV(-) cancers. Analysis of HNSCC TCGA datasets provide evidence for distinct alterations in expression of components of the NF-¿B and death pathways in HPV(+ and -) HNSCC. Previously, we have found that Birinapant, a novel SMAC mimetic that inhibits inhibitor of apoptosis proteins (IAPs), sensitizes a subset of HPV(-) HNSCC cell lines to death agonists like TNF-a and TRAIL. In this study, we have observed that Birinapant also sensitizes some (UPCI-SCC-90 and UM-SCC-47) but not all HPV(+) cell lines to TRAIL and TNF-a in vitro. The IC50 for Birinapant was under 50nM with TRAIL and TNF-a for UPCI-SCC-90 and UM-SCC-47 cell lines. To explore the therapeutic potential of enhancing TRAILR mediated death signaling in HPV(+) HNSCC cells, we investigated the effects of an agonistic polyclonal TRAILR2 antibody. Treatment of cells with TRAILR2 antibody alone shows little or no inhibitory effect on UPCI-SCC-90 and UM-SCC-47 cells in vitro. However, a combination of Birinapant and TRAILR2 antibody, and triple combination of Birinapant, TRAIL, and TRAILR2 antibody shows additive or synergistic effects to inhibit cell proliferation and induce cell death in a dose dependent manner.

Scientific Focus Area: Cancer Biology

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