Loss of miR-146a-5p contributes to ibrutinib resistance in mantle cell lymphoma

Resistance to Bruton's tyrosine kinase (BTK) inhibition represents a major clinical challenge in mantle cell lymphoma (MCL). While ibrutinib suppresses B-cell receptor signaling, patients eventually relapse, underscoring the need to elucidate non-genetic resistance mechanisms. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression, yet their contribution to ibrutinib resistance in MCL remains incompletely defined. To this end, we established three ibrutinib-resistant MCL cell line models through prolonged drug exposure and performed integrated miRNA and transcriptome profiling. Resistant cells exhibited a distinct miRNA signature characterized by downregulation of miRNAs targeting the MAPK-ERK and PI3K-AKT survival pathways, resulting in pathway hyperactivation. These findings were validated in patient-derived xenografts and clinical biopsy samples from ibrutinib-resistant patients. Pharmacological inhibition of these pathways effectively suppressed pathway activation, reduced mitochondrial activity, and induced apoptosis in resistant cells, with enhanced efficacy observed upon dual pathway targeting. Among deregulated miRNAs, miR-146a-5p was consistently reduced in resistant cell lines, PDX models, and patient samples. Restoration of miR-146a-5p expression resensitized resistant cells to ibrutinib. Promoter hypermethylation of miR-146a provides a potential epigenetic mechanism underlying its repression. Overall, these data identify miRNA-mediated activation of MAPK and PI3K signaling as epigenetic driver of ibrutinib resistance in MCL and support rational combination strategies to overcome therapeutic failure.