Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism.
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X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K (d) > 1 μM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells for death in an IAP-dependent manner, these findings support the development of Smac mimetics for IBC treatment.
Published Version (Please cite this version)
Allensworth, Jennifer L, Scott J Sauer, H Kim Lyerly, Michael A Morse and Gayathri R Devi (2013). Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat, 137(2). pp. 359–371. 10.1007/s10549-012-2352-6 Retrieved from https://hdl.handle.net/10161/12454.
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We are studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on adoptive transfer of tumor and viral antigen-specific T cells.
Our current clinical trials include phase I and II studies of immunotherapy for: patients with metastatic malignancies expressing CEA, pancreatic cancer, colorectal cancer, breast cancer, and ovarian cancer, and leukemias following HSCT. My clinical area of expertise is in gastrointestinal oncology, in particular, the treatment of hepatic malignancies, and malignant melanoma.
Key words: dendritic cells, immunotherapy, vaccines, T cells, gastrointestinal oncology, melanoma, hepatoma
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