Brigimadlin (BI-907828) and napabucasin (BBI608) cooperatively trigger apoptosis in chronic lymphocytic leukemia cells by simultaneous iİnhibition of MDM2 and STAT3.

BACKGROUND: Chronic lymphocytic leukemia (CLL) remains largely incurable, particularly in elderly or treatment-resistant patients. Although MDM2 inhibitors restore p53-mediated apoptosis in p53-functional CLL, single-agent activity is limited by resistance mechanisms. Signal transducer and activator of transcription 3 (STAT3) signaling also promotes CLL survival and immune evasion, suggesting that concurrent blockade of both pathways may enhance cell death.

METHODS AND RESULTS: Here, the synergistic potential of the oral MDM2 antagonist BI-907828 (brigimadlin) and the STAT3 inhibitor BBI608 (napabucasin) was evaluated in two CLL cell lines with distinct TP53 (Tumor Protein p53, the gene encoding p53 protein) status: p53-wild-type EHEB and p53-mutant/17p-deleted MEC-1. Monotherapy with BI-907828 induced marked p53 stabilization, upregulation of p21WAF1, PARP cleavage, and caspase-3/7 activation in EHEB cells, whereas MEC-1 cells remained unresponsive. BBI608 alone reduced cell viability in both lines in a dose-dependent manner, with its effect in MEC-1 cells suggesting a p53-independent mechanism. When combined, BI-907828 and BBI608 synergistically enhanced apoptotic markers in EHEB cells (δ synergy score > 17) but elicited no synergy in MEC-1, underlining the requirement for intact p53.

CONCLUSION: These findings establish a mechanistic rationale for the concurrent targeting of the MDM2 and STAT3 axes and provide preclinical evidence for a promising, non-genotoxic therapeutic strategy in p53-functional CLL. A limitation of this study is the lack of in vivo validation and clinical data, which are necessary to further assess the safety, optimal dosing, and efficacy, particularly in elderly or unfit patients with limited treatment options.