Abstract
Bruton tyrosine kinase (BTK) and BCL2 are key therapeutic targets in marginal zone lymphoma (MZL). We evaluated the novel BTK degrader tacabrutideg (BGB-16673) and the secondgeneration BCL2 inhibitor sonrotoclax, alone and in combination, in MZL models, including derivatives with acquired resistance to BTK, BCL2, and PI3K inhibitors. Tacabrutideg was evaluated for cytotoxicity, apoptosis, transcriptomic and protein changes, real-time cell growth, three-dimensional stromal co-culture, and activity in primary MZL samples. Combination studies included sonrotoclax, venetoclax, bendamustine, lenalidomide, rituximab, selinexor, and tazemetostat.Tacabrutideg showed single-agent activity in MZL cell lines, inducing BTK degradation and suppression of BCR signaling, MYC targets, and oxidative phosphorylation. Its biological effects largely overlapped with those of zanubrutinib while maintaining complete target degradation. Tacabrutideg inhibited PLCG2 and ERK phosphorylation, reduced cell growth in realtime assays, retained activity in three-dimensional stromal co-cultures, and suppressed growth and ERK phosphorylation in primary MZL samples. Combination studies identified the greatest benefit with sonrotoclax, venetoclax, bendamustine, lenalidomide, and rituximab. Sonrotoclax consistently outperformed venetoclax, exhibiting >10-fold greater potency in three MZL cell lines and synergizing with tacabrutideg across multiple models. The combination enhanced apoptosis through coordinated modulation of BCL2 family proteins, including BCL2, MCL1, and BCL-XL. Tacabrutideg demonstrates potent preclinical activity in MZL as a single agent and in combination regimens. Together with the superior activity of sonrotoclax, these findings provide a strong rationale for the clinical evaluation of dual BTK degradation and BCL2 inhibition in patients with MZL.