Combining BET inhibition with SMAC mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models

Second mitochondrial activator of caspase (SMAC) mimetics (SMACm) and bromodomain and extra-terminal domain (BET) inhibitors (BETi) are two distinct classes of novel anticancer therapeutics. So far, broad clinical benefit for either monotherapy has not been achieved, calling for effective combination strategies. We show that the combination of BI 891065, a monovalent oral SMACm antagonist of inhibitor of apoptosis protein 1 (cellular inhibitor of apoptosis protein 1 [cIAP1]), and BI 894999, a potent and selective oral BETi, significantly impaired cancer cell proliferation irrespective of tissue context. Interestingly, we observed various forms of cell death pointing at distinct, but functionally converging, modulation of cell death-promoting pathways. A multi-omic analysis using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and advanced flow cytometry of a syngeneic model of pancreatic ductal adenocarcinoma (PDAC) unveils distinct phenotypic correlations of augmented anti-tumor immunity and a substantially reduced immunosuppressive tumor microenvironment (TME). Collectively, this study presents BETi and SMACm as a promising drug combination for patients with cancer with a multi-layered impact on both tumor cell-intrinsic and TME-dependent mechanisms.

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Publication Details

Journal
Cell Reports Medicine
Published
2025-08-25
DOI
https://doi.org/10.1016/j.xcrm.2025.102313
Citations
1
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
0.81

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article

Combining BET inhibition with SMAC mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models

Johannes Popow, Daniel Gerlach, Anke Baum, Paula-Elena Traexler et al.
1 citations
Cell Reports Medicine
Protein Degradation and Inhibitors
0.81
article

Combining BET inhibition with SMAC mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models

Johannes Popow, Daniel Gerlach, Anke Baum, Paula-Elena Traexler, Ines Baumann, Regina Ruzicka, Ulrich Reiser, Mary Y. Murphy, Valeria Santoro, Jesse Lipp, Salvatore Siena, Martin Aichinger, Artem V. Artemov, Martina Miotto, Andreas Wernitznig, Florian Ebner, Alberto Bardelli, Ulrike Tontsch-Grunt, Ha Pham Thi Thanh, Mariangela Russo, Sebastian Carotta, Maria-Antonietta Impagnatiello, Robin Jacob, Reniqua House, Ksenija Slavic Obradovic
article en
1 citations

Abstract

Second mitochondrial activator of caspase (SMAC) mimetics (SMACm) and bromodomain and extra-terminal domain (BET) inhibitors (BETi) are two distinct classes of novel anticancer therapeutics. So far, broad clinical benefit for either monotherapy has not been achieved, calling for effective combination strategies. We show that the combination of BI 891065, a monovalent oral SMACm antagonist of inhibitor of apoptosis protein 1 (cellular inhibitor of apoptosis protein 1 [cIAP1]), and BI 894999, a potent and selective oral BETi, significantly impaired cancer cell proliferation irrespective of tissue context. Interestingly, we observed various forms of cell death pointing at distinct, but functionally converging, modulation of cell death-promoting pathways. A multi-omic analysis using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and advanced flow cytometry of a syngeneic model of pancreatic ductal adenocarcinoma (PDAC) unveils distinct phenotypic correlations of augmented anti-tumor immunity and a substantially reduced immunosuppressive tumor microenvironment (TME). Collectively, this study presents BETi and SMACm as a promising drug combination for patients with cancer with a multi-layered impact on both tumor cell-intrinsic and TME-dependent mechanisms.

Cell Reports MedicineVol. 6(9)
Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), IFOM (IT), Boehringer Ingelheim (Austria) (AT), Boehringer Ingelheim (United States) (US), University of Turin (IT)
Boehringer Ingelheim, Cancer Research UK, Fundación Científica Asociación Española Contra el Cáncer, Associazione Italiana per la Ricerca sul Cancro, Horizon 2020 Framework Programme, European Research Council
Openalex Percentile: Top 24%
Protein Degradation and Inhibitors
0.81
DOIOpen Access PDFOpenAlex
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