Abstract C20: In vitro effects of Debio 1143, a novel oral IAP inhibitor, in human SCCHN cell lines and tumor specimens.

Abstract

Abstract 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 (D1143, 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 aimed at evaluating D1143 activity as a single agent and in combination with TNF-α, TRAIL, cisplatin or carboplatin, in various SCCHN models. Materials and Methods: The antiproliferative effects of D1143 were evaluated in a panel of 5 human SCCHN cell lines by MTT assay. Baseline and phosphorylated protein levels were detected by Western blot analysis. 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 D1143 and/or 1 µM of platinum-based drug for 48 hours. Tumor samples were analyzed by immunohistochemistry (IHC) or immunofluorescence to visualize the effects of the treatment on various biomarkers of cell apoptosis, proliferation, and drug target engagement. Results: A panel of 5 SCCHN cell lines was characterized for the expression of c-IAP1/2, XIAP, Bcl2, LRIG1, and other proteins implicated in resistance to cell death. D1143 alone displayed limited antiproliferative activity in only one cell line (Detroit 562). However, two SCCHN cell lines were sensitive to D1143 and TRAIL combined (SQ20B and SCC15), three were sensitive to D1143 and TNF-α combined (SQ20B, SCC61, and Detroit 562), and one was resistant to both combinations (HEP2). In Detroit 562 sensitive cells, 10 µM D1143 induced sustained cIAP1/2 degradation after 15 minutes of exposure. In contrast, in the HEP2 insensitive cell line, D1143 induced slight and transient inhibition of cIAP1/2. IHC analyses revealed that ex vivo exposure to D1143 of tumor explants freshly resected from SCCHN patients decreased cIAP1 staining. Treatment of tumor samples with D1143 combined with cisplatin or carboplatin augmented the cleavage of caspase 3 compared to controls suggesting induction of apoptosis. Conclusion: In 4 out of 5 SCCHN cell lines, D1143 induced cIAP1/2 degradation and potentiated TNF-α or TRAIL-induced antiproliferative effects. D1143 combined with carboplatin and cisplatin in SCCHN patient samples induced caspase 3-dependent apoptosis. D1143 in combination with conventional chemotherapies may be considered as a potential treatment for SCCHN patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C20. Citation Format: Marie Serova, Annemilaï Tijeras-Raballand, Sebastien Albert, Sandrine Faivre, Eric Raymond, Anne Vaslin, Claudio Zanna, Gregoire Vuagniaux, Armand de Gramont. In vitro effects of Debio 1143, a novel oral IAP inhibitor, in human SCCHN cell lines and tumor specimens. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C20.