Abstract 2055: The SMAC-mimetic Debio 1143 efficiently enhanced chemo and radiotherapy in head and neck squamous cell carcinoma models

Purpose/objectives: Resistance of tumor cells to chemotherapy (CT) or radiotherapy (RT)-induced apoptosis is a major problem in the treatment of head and neck squamous cell carcinoma (HNSCC), and highlights the need for new therapeutic strategies. The small molecule Debio 1143 (D1143) (a.k.a. SM-406 or AT-406) is a potent orally-active, monovalent Smac-mimetic designed to promote programmed cell death in tumor cells by blocking the activity of inhibitor of apoptosis proteins (IAPs) to create conditions in which apoptosis can proceed. This study aimed to test the efficacy of D1143 as a single agent and/or in combination with CT or RT in HNSCC models. Materials and methods: The effect of D1143 was assessed by the colony forming assay on a panel of HNSCC patient-derived xenograft (PDX) tumors and established cell lines. Tumor cells were incubated at various concentrations of D1143 (ranging from 0.1 to 30 μM) and treated with increasing doses of radiation or cisplatin. Cells were cultured for a minimum of 10 days before being fixed and stained. The number of surviving colonies was then recorded and compared to an untreated group. In parallel, various treatment sequences were tested, (before, during or post-irradiation) to determine the effect of D1143 on primary apoptosis (early, pre-mitotic apoptosis) and secondary apoptosis (late, post-mitotic reproductive cell death). The in vivo chemo/radiosensitizing effect of oral treatment with D1143 was further evaluated in nude mice bearing HNSCC tumor xenografts. Results: D1143 alone selectively inhibited colony formation of several PDX tumors and established cell lines. In addition, combination experiments found D1143 to be highly effective in enhancing cell death induced by RT or cisplatin. A synergistic effect of D1143 was observed in the majority of the tested cell lines treated by RT, whereas D1143 enhanced the activity of cisplatin in a subset of tumor cells. Interestingly, the radiosensitizing effect of D1143 was preeminent when cells were co-incubated with D1143 24 hours after irradiation, showing that D1143 efficiently impacts late apoptosis due to mitotic catastrophe and/or other cell death events that arise after irradiation. In mice bearing HNSCC radio-resistant tumors, D1143 given orally in combination with RT delayed tumor growth for more than 40 days when compared to RT only and for more than 60 days when compared to vehicle only. In addition, oral administration of D1143 showed additive to synergistic