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.