Abstract
Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy of the preclinical Smac-mimetic compound A and the clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity in triple-negative breast cancer (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using in vivo PDX models of TNBC and estrogen receptor-positive (ER+) breast cancer. Birinapant exhibited single agent activity in all TNBC PDX models and augmented response to docetaxel, the latter through induction of TNF. Transcriptomic analysis of TCGA datasets revealed that genes encoding mediators of Smac-mimetic-induced cell death were expressed at higher levels in TNBC compared with ER+ breast cancer, resulting in a molecular signature associated with responsiveness to Smac mimetics. In addition, the cell death complex was preferentially formed in TNBCs versus ER+ cells in response to Smac mimetics. Taken together, our findings provide a rationale for prospectively selecting patients whose breast tumors contain a competent death receptor signaling pathway for the further evaluation of birinapant in the clinic.
Highlights
These authors contributed : Delphine Merino, Goknur Giner, François VaillantThese authors jointly supervised this work: Jane E
Cells were treated for 5 h with 1 μM of CompA (CpA) and with 5 μM of the caspase inhibitor IDN-6556 (Casp inh) to stabilize the complex. d Cell viability assessed using CellTiter-Glo of the estrogen receptor (ER)+ patient-derived xenograft (PDX)-23 and the triple-negative breast cancer (TNBC) PDX-110 tumor cells treated for 24 h with 1 μM CompA (CpA) ±10 μM of Q-VD-OPh (Q-VD) or 50 μM Necrostatin (NEC) or 10 μg/ml of blocking antiTNF or 10 μg/ml of blocking anti-TRAIL. a, b, d Results are presented as percentages of untreated cells
We have explored the inhibitor of apoptosis (IAP) inhibitor birinapant as a possible targeting strategy and found that single agent therapy produces a therapeutic response in TNBC PDX models
Summary
These authors contributed : Delphine Merino, Goknur Giner, François Vaillant. These authors jointly supervised this work: Jane E. The Smac-mimetic LCL161 (Novartis) has been studied in combination with paclitaxel in a randomized phase II neoadjuvant study in TNBC, where higher pathological Clinical Responses were observed in patients with a TNFα gene expression signature (GS), albeit with significant toxicity. This signature, derived through in silico analysis of LCL161-sensitive versus refractory cell lines, features high TNF and RIPK1 expression and is present in 26% of TNBC [20]. Protein expression profiling revealed that cIAP1 levels were higher in ER+ than TNBC This subtype remained largely resistant to induced cell death, even though birinapant was able to degrade most of cIAP1 in ER+ breast cancer cells. Our findings reveal a targetable subset of breast cancers that include TNBC and possibly some ER+ breast cancers
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