Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.

Simple Summary Recurrent ovarian cancer is difficult to treat due to the development of chemotherapy resistance. This resistance develops through multiple mechanisms to include the avoidance of cell death by cancer cells. Prior studies have shown birinapant, a second mitochondrial activator of caspases (SMAC) mimetic drug, to be promising in overcoming this acquired resistance. Despite good tolerability, however, therapy with single-agent birinapant exhibited minimal anti-cancer activity in women with recurrent ovarian cancer. By using a high-throughput drug screen we were able to identify potential therapeutic agents that augment birinapant activity, with docetaxel emerging favorably due to its marked synergy and known utility in the recurrent ovarian cancer setting. We showed that this synergy is the result of several complementary molecular pathways and hope to highlight the promising potential of this therapeutic drug combination for clinical testing where treatment options are often limited. Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-alpha upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.