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Title: Targeting triple-negative breast cancers with the Smac-mimetic birinapant.
Austin Authors: Lalaoui, Najoua;Merino, Delphine;Giner, Goknur;Vaillant, François;Chau, Diep;Liu, Lin;Kratina, Tobias;Pal, Bhupinder;Whittle, James R;Etemadi, Nima;Berthelet, Jean;Gräsel, Julius;Hall, Cathrine;Ritchie, Matthew E;Ernst, Matthias ;Smyth, Gordon K;Vaux, David L;Visvader, Jane E;Lindeman, Geoffrey J;Silke, John
Affiliation: Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, 3010, Australia
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
School for Cancer Medicine La Trobe University, Heidelberg, VIC, 3084, Australia
School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, 3010, Australia
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
Issue Date: 27-Apr-2020 2020-04-27
Publication information: Cell death and differentiation 2020; online first: 27 April
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.
DOI: 10.1038/s41418-020-0541-0
ORCID: 0000-0002-0165-3324
PubMed URL: 32341449
Type: Journal Article
Appears in Collections:Journal articles

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