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

Alexey Danilov1, Sonia Rodriguez-Rodriguez1, Dan Vuong1

  • 1City of Hope.

Research Square
|May 18, 2026
PubMed

Insights

Cyclin-dependent kinase 5 (CDK5) drives resistance to Bruton tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma (MCL). Targeting CDK5 may overcome BTKi resistance by modulating the unfolded protein response pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Mechanisms of resistance to Bruton tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma (MCL) are not fully understood.
  • Cyclin-dependent kinase 5 (CDK5) is implicated in various cellular processes, including proliferation and signaling pathways.

Purpose of the Study:

  • To investigate the role of CDK5 in BTKi resistance in MCL.
  • To elucidate the molecular mechanisms by which CDK5 contributes to BTKi resistance.

Main Methods:

  • Analysis of CDK5 expression in BTKi-resistant MCL cell lines and patient samples.
  • Genetic and pharmacologic manipulation of CDK5 in MCL cell lines.
  • Murine xenograft models to assess the impact of CDK5 on tumor growth and survival.
  • Mass spectrometry to identify CDK5-interacting proteins and affected pathways.
  • Investigation of the unfolded protein response (UPR) pathway involving IRE1α and Xbp1.

Main Results:

  • CDK5 was upregulated in ibrutinib-resistant MCL cells and associated with poor outcomes in patients.
  • CDK5 promoted MCL cell proliferation and ibrutinib resistance in vitro and in vivo.
  • CDK5 interacted with BTK and modulated B-cell receptor and BAFF signaling.
  • CDK5 influenced cell cycle and metabolism, affecting kinase activities including Src.
  • CDK5 complexed with IRE1α and Xbp1, promoting UPR and contributing to ibrutinib resistance.
  • Xbp1 knockdown resensitized MCL cells to ibrutinib.

Conclusions:

  • CDK5 is a key mediator of BTKi resistance in MCL.
  • CDK5 promotes resistance by regulating the XBP1/IRE1α axis of the UPR pathway.
  • CDK5 represents a potential therapeutic target for overcoming BTKi resistance in MCL.

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