The Novel SMAC Mimetic Birinapant Exhibits Potent Activity against Human Melanoma Cells

Purpose: Inhibitor of apoptosis proteins (IAP) promote cancer cell survival and confer resistance to therapy. We report on the ability of second mitochondria-derived activator of caspases mimetic, birinapant, which acts as antagonist to cIAP1 and cIAP2, to restore the sensitivity to apoptotic stimuli such as TNF-alpha in melanomas. Experimental Design: Seventeen melanoma cell lines, representing five major genetic subgroups of cutaneous melanoma, were treated with birinapant as a single agent or in combination with TNF-alpha. Effects on cell viability, target inhibition, and initiation of apoptosis were assessed and findings were validated in 2-dimensional (2D), 3D spheroid, and in vivo xenograft models. Results: When birinapant was combined with TNF-alpha, strong combination activity, that is, neither compound was effective individually but the combination was highly effective, was observed in 12 of 18 cell lines. This response was conserved in spheroid models, whereas in vivo birinapant inhibited tumor growth without adding TNF-alpha in in vitro resistant cell lines. Birinapant combined with TNF-alpha inhibited the growth of a melanoma cell line with acquired resistance to BRAF inhibition to the same extent as in the parental cell line. Conclusions: Birinapant in combination with TNF-alpha exhibits a strong antimelanoma effect in vitro. Birinapant as a single agent shows in vivo antitumor activity, even if cells are resistant to single agent therapy in vitro. Birinapant in combination with TNF-alpha is effective in a melanoma cell line with acquired resistance to BRAF inhibitors. Clin Cancer Res; 19(7); 1784-94. (C)2013 AACR.