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.