The deregulation of pro- and anti-survival signalling pathways leads to escape from cell death and contributes to a poor response to chemotherapy and relapse in malignancies. Exploiting recently identified novel cell death mechanisms such as necroptosis represents an attractive strategy to eradicate such resistant tumor cells. Necroptosis occurs without caspase activation and relies on distinct protein-protein interactions regulated by receptor-interacting protein kinase 1, RIP1. RIP1 is held in check by the inhibitor of apoptosis proteins (IAPs). Depletion of IAPs using small-molecule SMAC mimetics (SM) can potently induce a switch from RIP1-controlled survival to cell death.

Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.