IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas

  • bioRxiv. 2025 May 10:2025.05.07.652612. doi: 10.1101/2025.05.07.652612.
Alberto J Arribas ,  Francesca Guidetti ,  Eleonora Cannas ,  Luciano Cascione ,  Sara Napoli ,  Giulio Sartori ,  Federica Fuzio ,  Emma Pesenti ,  Chiara Tarantelli ,  Filippo Spriano ,  Antonella Zucchetto ,  Francesca M Rossi ,  Alessio Bruscaggin ,  Andrea Rinaldi ,  Manuel Castro de Moura ,  Sandra Jovic ,  Andrea Raimondi ,  Roberta Bordone Pittau ,  Lodovico Terzi di Bergamo ,  Xiaofei Ye ,  Anastasios Stathis ,  Yaacov Ben-David ,  Qiang Pan-Hammarström ,  Federico Simonetta ,  Georg Stussi ,  Emanuele Zucca ,  Valter Gattei ,  Jennifer R Brown ,  Manel Esteller ,  Davide Rossi ,  Francesco Bertoni
PMID: 40654846 DOI: 10.1101/2025.05.07.652612
Abstract

Introducing Bruton's tyrosine kinase (Btk) inhibitors has significantly improved outcomes for patients with B-cell malignancies and autoimmune disorders. However, resistance, either primary or acquired, remains a major clinical challenge. To better understand the underlying resistance mechanisms to Btk inhibitors, we established an ibrutinib-resistant model from a patient-derived splenic marginal zone lymphoma (MZL) cell line (VL51) through prolonged drug exposure. Resistant cells exhibited a 15-fold increase in ibrutinib's IC50, along with distinct morphological changes, mitochondrial activation, and cross-resistance to covalent, non-covalent Btk inhibitors and Btk degraders. Integrated transcriptomic, epigenomic, and proteomic analyses identified overexpression and secretion of IL-16 as a key feature of resistance, driven by chromatin remodeling and activation of the FLI1 transcription factor. IL-16 conferred ibrutinib resistance via CD9-mediated activation of the NF-κB and Akt signaling pathways and was found to be elevated in the serum of ibrutinib-refractory CLL patients. Functional studies showed that targeting the IL-16/CD9 axis using neutralizing antibodies or CD9-binding Peptides restored sensitivity to Btk inhibitors and R-CHOP chemotherapy in MZL, mantle cell lymphoma, and Diffuse Large B-cell Lymphoma models. These findings reveal a novel, targetable resistance mechanism with potential therapeutic implications for overcoming Btk inhibitor resistance in B-cell lymphomas.

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