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

Abstract

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. Experimental study using human HNSCC cell lines in vitro and xenograft mouse model in vivo. 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. Birinapant, alone or in combination with TNFα or TRAIL, decreased cell density in cell lines, with IC50 s 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. 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.