Journal article

Targeting triple-negative breast cancers with the Smac-mimetic birinapant

Najoua Lalaoui, Delphine Merino, Goknur Giner, Francois Vaillant, Diep Chau, Lin Liu, Tobias Kratina, Bhupinder Pal, James R Whittle, Nima Etemadi, Jean Berthelet, Julius Grasel, Cathrine Hall, Matthew E Ritchie, Matthias Ernst, Gordon K Smyth, David L Vaux, Jane E Visvader, Geoffrey J Lindeman, John Silke

Cell Death & Differentiation | NATURE PUBLISHING GROUP | Published : 2020

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 d..

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Grants

Awarded by Worldwide Cancer Research grant


Awarded by Victoria Cancer Agency MidCareer Fellowship


Awarded by Cure Cancer foundation


Awarded by NHMRC


Awarded by Leukemia and Lymphoma Society SCOR grant


Awarded by Australian Government NHMRC IRIISS


Awarded by Cancer Australia


Funding Acknowledgements

We thank former employees of TetraLogic Pharmaceuticals for support and discussions, in particular Stephen Condon, C. Glenn Begley, Mark McKinlay, Sri Chunduri, and Chris Benetatos. We thank Kevin Liu for animal care. Coded breast tumor samples were provided by the Victorian Cancer Biobank (supported by the Victorian Government). NL was supported by the Worldwide Cancer Research grant 15-0042, by a Victoria Cancer Agency MidCareer Fellowship #17030 and by the Cancer Australia and Cure Cancer foundation Project Grant #1145588. DM was supported by the National Breast Cancer Foundation. GKS is supported by an NHMRC Research Fellowship #1058892. DLV is supported by an NHMRC Research Fellowship #1020136 and the Leukemia and Lymphoma Society SCOR grant #7001-13. JEV is supported by an NHMRC Research Fellowship #1037230. GJL is supported by an NHMRC Fellowship #1078730. JS is supported by an NHMRC Research Fellowship #1107149. This work was funded by NHMRC grants #1054618, #1025594, #1046984, #1016701, #1101378 and #1113133, and made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (9000433).