Molecular and structural basis of pan-resistance to BTK targeting therapies via BTK A428D mutation

作者：Quinlan Sievers, Hao Lu, Allison Cool, Stefan Gajewski, Tim Kong, Mark Noviski, Emel Ficici, Ratul Mukerji, James N. Iuliano, Jordan Ye, Mateo Sanchez Garcia de los Rios, Hugo Bousquet, Sarah Whelan, May Tan, Chris B. Phelps, Xiaoli Mi, Jahan Rahman, Samantha Sekeres, Erica Lamkin, Eduardo Bravo, Mark D. Ewalt, Anthony R. Mato, Lindsey E. Roeker, Justin Taylor, Meghan C. Thompson, Gwenn M. Hansen, Omar Abdel‐Wahab · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-2102 · 被引用次数：1 · 研究领域：Chronic Lymphocytic Leukemia Research、Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways

Abstract BTK degraders promote proteasomal degradation of BTK and can overcome resistance to covalent and noncovalent BTK inhibitors in patients with relapsed CLL. Currently the molecular basis for BTK degrader resistance is unknown. We therefore set out to understand BTK degrader resistance based on observations from the phase 1 trial of zelebrudomide (NX-2127) (NCT04830137), the first BTK degrader to enter clinical studies. Targeted 500-gene sequencing was performed on blood and/or tissue from four CLL patients treated with zelebrudomide. In one patient previously treated with chemoimmunotherapy, ibrutinib, venetoclax, and pirtobrutinib, BTK A428D was detected in the baseline blood sample with variant allele frequency (VAF) of <2%, along with BTK V416L (13%) and mutations in TP53 (60%) and SF3B1 (37%). Following daily treatment with 100mg zelebrudomide and subsequent dose escalation to 200mg, at 6 months the VAF of all four mutations increased, with BTK A428D VAF increasing to 6% in the blood and 29% in a lymph node. BTK A428D was detected at baseline but not at progression in a second patient. To evaluate the impact of BTK A428D on drug response, we transduced BTK-dependent TMD8 cells with BTK WT, C481S, L528W, and A428D, and found that BTK A428D uniquely conferred resistance to all FDA-approved BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) as well as three BTK degraders under clinical evaluation (zelebrudomide, bexobrutideg, BGB-16673). To ...