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


Lalaoui, N; Merino, D; Giner, G; Vaillant, F; Chau, D; Liu, L; Kratina, T; Pal, B; Whittle, JR; Etemadi, N; Berthelet, J; Grasel, J; Hall, C; Ritchie, ME; Ernst, M; Smyth, GK; Vaux, DL; Visvader, JE; Lindeman, GJ; Silke, J
2020-04-27
Cell Death and Differentiation
Journal epub ahead of print
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.
NPG
Inflammation; Bioinformatics; Cancer Biology and Stem Cells; Advanced Technology and Biology; Epigenetics and Development
10.1038/s41418-020-0541-0
32341449
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2020-05-04 10:30:33 Last Modified 2020-05-04 10:47:17