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SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

 

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The overexpression of IAP proteins is a well-known phenomenon in ovarian cancer and is strongly associated with poor patient survival. Recurrent ovarian cancers exhibit resistance to apoptosis, in part due to dysregulated IAP proteins. In this context, SMAC mimetics have been developed to suppress the functions of IAP proteins and restore apoptotic pathways, leading to tumor death. However, despite demonstrating on-target activity, a phase 2 clinical trial of the SMAC mimetic birinapant in women with recurrent ovarian cancer showed minimal drug response.

To overcome this limitation, the authors conducted a high-throughput screening matrix to identify synergistic drug combinations with birinapant. They found that the combination of SMAC mimetics with an HDAC inhibitor showed remarkable synergy, both in vitro and in vivo. The mechanism of this synergy involves multiple convergent pathways, including increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling.

These findings suggest that the combination of SMAC mimetics and HDAC inhibitors could be a promising therapeutic strategy for recurrent ovarian cancer, where treatment options are limited. Future clinical trials will be needed to evaluate the safety and efficacy of this combination therapy in humans.

Related Products

Cat.No. Product Name Information
S7015 Birinapant Birinapant is a SMAC mimetic antagonist, mostly to cIAP1 with Kd of <1 nM in a cell-free assay, less potent to XIAP. Birinapant helps to induce apoptosis in latent HIV-1-infected cells. Phase 2.

Related Targets

HIV IAP Apoptosis related