Combination effects of SMAC mimetic birinapant with TNFα, TRAIL, and docetaxel in preclinical models of HNSCC

Objectives/Hypothesis: Head and neck squamous cell carcinoma (HNSCC) cells are resistant to cell death induced by tumor necrosis factor ligands such as tumor necrosis factor α (TNFα) or TNF-related apoptosis-inducing ligand (TRAIL) and cytotoxic chemotherapies. Recently, genetic alterations in cell death pathways, including inhibitor of apoptosis proteins, have been demonstrated in HNSCC. We investigated the effects of birinapant, a novel, second mitochondria-derived activator of caspases (SMAC)-mimetic that targets inhibitor of apoptosis proteins, alone and in combination with TNFα, TRAIL, or chemotherapy docetaxel. Study Design: Experimental study using human HNSCC cell lines in vitro and xenograft mouse model in vivo. Methods: A panel of HNSCC cell lines with varying genetic alterations in cell death pathway components were treated with birinapant±TNFα, TRAIL, and docetaxel and were assessed for effects on cell density, cell cycle, and death. Synergism was determined at varying concentrations of treatments using the Chou-Talalay method. Combination studies using birinapant±docetaxel were performed in a xenograft mouse model. Results: Birinapant, alone or in combination with TNFα or TRAIL, decreased cell density in cell lines, with IC50s ranging from 0.5 nM to>1 μM. Birinapant alone or with TNF significantly increased subG0 cell death in different lines. Docetaxel showed synergism with birinapant±TNFα in vitro. Birinapant monotherapy-inhibited growth in a tumor xenograft model resistant to docetaxel, and combination treatment further delayed growth. Conclusions: Birinapant alone or in combination with TNFα or TRAIL and docetaxel decreased cell density, increased cell death, and displayed antitumor activity in a preclinical HNSCC xenograft exhibiting aberrations in cell death pathway components and docetaxel resistance.