Birinapant Enhances Gemcitabine's Antitumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway–Dependent Apoptosis

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy. Therefore, IAPs have become attractive molecular targets for cancer treatment. Here, we first investigated the antitumor efficacy of birinapant (TL32711), a biindole-based bivalent mimetic of second mitochondria-derived activator of caspases (SMACs), in TNBC. We found that birinapant as a single agent has differential antiproliferation effects in TNBC cells. We next assessed whether birinapant has a synergistic effect with commonly used anticancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine, in TNBC. Among these tested drugs, gemcitabine showed a strong synergistic effect with birinapant. Birinapant significantly enhanced the antitumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the antitumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.

A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology

“…We found that birinapant showed potent activity in certain TNBC organoids, and this was validated in PDXs. Others have shown that birinapant has selective activity for TNBC compared to ER + breast cancers 34,35 , and a similar SMAC mimetic (LCL161) combined with paclitaxel showed clinical activity only in TNBCs expressing a TNFα signature 36 . These data demonstrate that unbiased screening in PDxOs can identify experimental agents with clinical activity in particular cancer subtypes.…”

Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy

“…Among the two families of known apoptosis regulators (IAP and Bcl-2 families of proteins), XIAP is considered the most potent inhibitor of cell death and an attractive therapeutic target due to its ability to suppress caspase activation via both intrinsic and extrinsic pathways and its ability to act as a signaling intermediate in tumor cell survival, immune and inflammatory pathways [ 17 , 44 ]. Based on strong evidence that XIAP expression in cancer cells promotes resistance to chemotherapy and radiation as well as elicit anti-cancer immune responses, the past decade has seen development of XIAP-specific targeting using RNA approaches [ 45 , 46 , 47 , 48 , 49 ], pan-IAP peptidomimetics, and small molecule inhibitors [ 17 , 19 , 50 , 51 , 52 , 53 ]. In particular, Smac mimetics have been instrumental in revealing the role for IAPs in regulating TNF receptor signaling [ 54 ] and have shown promising results in sensitizing cancer cell lines to conventional chemotherapies by occupying the BIR domains that normally interact with caspases [ 55 ].…”

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

“…We found that birinapant, a SMAC mimetic, showed potent activity in certain TNBC organoid models, and this was validated in PDX models. Indeed, others have recently shown that birinapant has selective activity for TNBC as compared to ER+ breast cancers 62, 63 , and a similar SMAC mimetic (LCL161) combined with paclitaxel showed clinical activity in the neoadjuvant setting, but only in TNBCs expressing a TNFalpha signature 64 . These data demonstrate that screening our human breast cancer PDxO collection can identify new experimental agents that can have clinical activity in particular breast cancer subtypes.…”