Cyclin-Dependent Kinase 5 Contributes to Bruton's Tyrosine Kinase Inhibitor Resistance via the IRE1α/XBP1 Axis in Mantle Cell Lymphoma

The mechanisms of resistance to Bruton tyrosine kinase inhibitors (BTKi) in MCL are not well understood. We found that cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, was upregulated in ibrutinib-resistant MCL cell lines and in primary MCL cells obtained from patients who progressed on BTKi. Furthermore, primary MCL cells upregulated CDK5 in BAFF/CD40L stromal conditions, and CDK5 mRNA overexpression in primary MCL tumors was associated with inferior outcomes. Genetic and pharmacologic (GFB-12811) manipulation of CDK5 in MCL cell lines revealed that CDK5 contributed to proliferation and ibrutinib resistance in vitro, while engineered expression of CDK5 in JeKo-1 cells shortened survival in a murine xenograft model. CDK5 was upregulated by B-cell receptor and BAFF signaling and complexed with Btk. Mass spectrometry analysis of CDK5-manipulated cells revealed that cell cycle and metabolism-related pathways were most affected by CDK5; 29 kinases were differentially active, and Src kinase activity correlated with CDK5 expression. CDK5 complexed with IRE1α and Xbp1, promoted IRE1α phosphorylation and increased Xbp1 levels thus facilitating unfolded protein response. Meanwhile, Xbp1 knockdown resensitized MCL cells to ibrutinib. Collectively, CDK5 promotes BTKi resistance via modulation of the XBP1/IRE1α axis of the UPR pathway and represents a potential therapeutic target in MCL.