Researchers paired a drug that erases a lymphoma protein with a BCL2 blocker — and killed drug-resistant cells

A next-generation BCL2 inhibitor called sonrotoclax was more than ten times as potent as venetoclax against marginal zone lymphoma cells in lab dishes, and the effect sharpened when paired with a "BTK degrader" that physically destroys its target protein, according to a paper in Haematologica.

Marginal zone lymphoma (MZL) is a slow-growing B-cell cancer that usually responds to treatment but frequently relapses. The next round of therapy is harder, because tumors that return often resist the targeted drugs, BTK inhibitors and BCL2 blockers, that worked the first time.

Tacabrutideg (BGB-16673) is a "degrader" rather than a conventional inhibitor. Instead of merely blocking BTK, it tags the protein for disposal by the cell's own recycling machinery. The authors report that single-agent tacabrutideg shut down BTK signaling in MZL cells, with effects that mostly overlapped with zanubrutinib, and that its potency held in three-dimensional stromal co-cultures and in primary patient samples.

The combination is the headline result. Sonrotoclax beat venetoclax by more than tenfold across three MZL cell lines, and pairing it with tacabrutideg produced synergistic apoptosis, per the abstract. The cell lines were engineered to resist BTK, BCL2, and PI3K inhibitors, the same kind of resistance that defeats single drugs in patients. The authors frame the findings as a rationale for clinical evaluation, not evidence of patient benefit. An earlier version appeared as a bioRxiv preprint in November 2025.