Investigating mechanism of resistance to ibrutinib in Mantle Cell Lymphoma

Abstract

Introduction Mantle Cell Lymphoma (MCL) comprises a unique group of B-cell non-Hodgkin lymphoma, which is characterised as "aggressive lymphoma" with poor diagnosis and considerable clinical heterogeneity. The Bruton tyrosine kinase (BTK) inhibitor Ibrutinib is the recommended drug for the treatment of MCL. However, some patients are resistant to Ibrutinib, hence, it is important to understand the molecular mechanism influencing the Ibrutinib response. The cell lines REC1 (Ibrutinib-sensitive) and G519 (Ibrutinib-resistant) were used in this study. Method The data were analysed using several proteomic approaches, such as Uniprot ID to check the protein names, Reactome to analyse the cell line pathways, Retrieve/ID mapping – UniProt to convert the Uniprot ID to gene names, String to predict the protein-protein interactions, Cytoscape to extensively visualise the pathways and InteractiVenn to visualise the matches and differences in the cell line pathway lists. Result Several molecular pathways contribute to the pathogenesis of MCL, for example, the pathways in the all lists (REC1+G519), (G519) and (REC1) are L13a-mediated translational silencing of ceruloplasmin expression and mRNA splicing, while pathways represented in (REC1+G519) list are folding of actin by CCT/TriC and eukaryotic translation initiation. The pathways in the (G519) list are GTP hydrolysis and joining of the 60S ribosomal subunit, glycolysis, and the citric acid cycle (TCA cycle), whereas pathways involved in the (REC1) list are mRNA 3’-end processing.

Conclusion The drug Ibrutinib drug has considerably improved the treatment of MCL but a better understanding of the mechanism involved in primary and acquired resistance to therapeutic drugs is extremally important to obtain better treatment outcomes. This study provides further information which could be used in further studies to target the pathways that reflects an abnormality that induces resistance.