Background: Resistance to radiotherapy and chemotherapy-induced apoptosis is a hallmark of cancer. Inhibitors of apoptosis proteins (IAPs) are negative modulators of apoptosis frequently expressed in various cancers, and, as such, attractive targets to overcome resistance to cancer therapy. The oral SMAC mimetic Debio 1143 (a.k.a AT-406), an antagonist of multiple IAPs (cIAP1/2 and XIAP), is currently investigated in a Phase I oncology clinical trial. This study evaluated Debio 1143 activity as a single agent, and in combination with TNF-α, TRAIL, cisplatin or carboplatin, in various tumor models of squamous cell carcinoma of the head and neck (SCCHN).

Materials and Methods: The antiproliferative effect of Debio 1143 was evaluated by MTT assay in human SCCHN cell lines SQ20B, SCC61, Hep2 and Detroit 562. The extent of apoptotic cell death was characterized by Western blot for cleaved caspase 3 and PARP. Tumor samples from SCCHN patients were surgically resected and cut into 300 µm thick slices using a tissue slicer (TIPCAN®). Each slice was exposed to 10 µM Debio 1143 and/or 1 µM of platinum-based drug for 48 hours. Tumor explants from 9 SCCHN patients were analyzed by immunohistochemistry or immunofluorescence to visualize the effects of treatment on various biomarkers of cell apoptosis, proliferation and drug target engagement.

Results: Debio 1143 alone displayed limited antiproliferative activity in SCCHN cell lines. The addition of TRAIL or TNF-α potentiated the antiproliferative effects of Debio 1143 in 1 cell line (SQ20B) and in 3 cell lines (SQ20B, SCC61 and Detroit 562), respectively. Combining Debio 1143 with TNF-α induced cleavage of caspase 3 and PARP, suggesting induction of apoptosis. Exposure of fresh SCCHN tumor explants to Debio 1143 reduced c-IAP1 staining. Combination of Debio 1143 with cisplatin or carboplatin induced caspase 3 activation, suggesting apoptosis. Large necrotic areas were also found on tissue samples after combination therapy.

Conclusion: In 3 out of 4 SCCHN cell lines, Debio 1143 potentiated TNF-α or TRAIL-induced antiproliferative effects. Debio 1143 combined with carboplatin and cisplatin induced caspase 3-dependent apoptosis in SCCHN patient tumor samples. Debio 1143 in combination with conventional chemotherapies could be a potential treatment for SCCHN patients.

Citation Format: Marie Serova, Annemilai Tijeras-Raballand, Sebastien Albert, Sandrine Faivre, Eric Raymond, Anne Vaslin, Claudio Zanna, Grégoire Vuagniaux, Armand de Gramont. Effects of Debio 1143, a novel oral IAP inhibitor, in monotherapy and in combination with platinum drugs in human SCCHN tumor specimens. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2014-2752