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

journal contribution
posted on 11.12.2020, 00:36 by N Lalaoui, Delphine Merino, G Giner, F Vaillant, D Chau, L Liu, T Kratina, Bhupinder Pal, JR Whittle, Nima Etemadi, Jean Berthelet, J Gräsel, C Hall, ME Ritchie, Matthias Ernst, GK Smyth, David Vaux, JE Visvader, GJ Lindeman, John Silke
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare. 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.

Funding

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).

History

Publication Date

01/10/2020

Journal

Cell Death and Differentiation

Volume

27

Issue

10

Pagination

13p. (p. 2768-2780)

Publisher

Nature Publishing Group

ISSN

1350-9047

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