Abstract 410: The BTK degrader BGB-16673 shows anti-tumor activity in marginal zone lymphoma models

Abstract Introduction: Targeting the B cell receptor (BCR) signaling with BTK and PI3K inhibitors is efficacious in treating patients with lymphoid tumors, including marginal zone lymphoma (MZL). Unfortunately, resistance occurs, indicating the need for combinations and novel approaches. BGB-16673 is a first-in-class cereblon-mediated BTK degrader currently in phase 1 for refractory/relapsed B cell lymphoma patients, including MZL. Here, we assessed BGB-16673 in MZL models as a single agent to provide the rationale for future trials in MZL patients. Methods: Effect on cell viability was assessed by MTT assay after 5 days of exposure to increasing concentrations of compounds or DMSO (control) in MZL cell lines and in cell lines with secondary resistance to idelalisib (n.=2), copanlisib (n.=1), ibrutinib (n.=2), and copanlisib/venetoclax. Analyses included apoptosis and cell cycle analysis by flow cytometry, immunoblotting, and RNA-Seq. Results: Six MZL cell lines (SSK41, Karpas1718, VL51, HC1, HAIRM, and ESKOL) were treated with the BTK degrader BGB-16673 at a concentration of up to 10μM. The BTK degrader was very active in 2 models (SSK41, IC50=0.1 nM; Karpas1718, 1.7 nM). VL51 achieved a maximal reduction in proliferation of 25% at 10 nM. Less than 20% of the reduction was observed in HC1, HAIRM and ESKOL. The activity of BGB-16673 did not differ from the BTK inhibitor zanubrutinib and, accordingly, was limited in cells resistant to ibrutinib (n.=2), idelalisib (n.=2), copanlisib (n.=1), and copanlisib/venetoclax (n.=2). BGB-16673 induced apoptosis and cell cycle arrest in sensitive Karpas1718 and SSK41. It importantly inhibited p-BTK(Tyr223) and decreased total BTK protein levels in all six cell lines. RNA-Seq was performed on Karpas1718 exposed to BGB-16673, zanubrutinib or DMSO. Both molecules down-regulated the BCR-TLR-NF-κB signaling pathway, MYC target genes, and upregulated genes involved in DNA damage. Oxidative phosphorylation, commonly associated with resistance to multiple therapies, was repressed by BGB-16673 but upregulated by zanubrutinib. Conclusions: Its ability to degrade BTK protein and its antitumor activity position the BTK degrader BGB-16673 as a promising candidate for further development in MZL patients. Citation Format: Alberto J. Arribas, Elisa Civanelli, Camilla Scalise, Luciano Cascione, Andrea Rinaldi, Davide Rossi, Emanuele Zucca, Francesco Bertoni. The BTK degrader BGB-16673 shows anti-tumor activity in marginal zone lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 410.