Pleiotropic action of novel Bruton's tyrosine kinase inhibitor BGB-3111 in mantle cell lymphoma

Carrie J. Li, Changying Jiang, Yang Liu, Taylor Bell, Wencai Ma, Yin Ye, Shengjian Huang, Hui Guo, Hui Zhang, Lai Wang, Jing Wang, Krystle Nomie, Liang Zhang, Michael Wang

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Bruton's tyrosine kinase (BTK) is a key mediator of BCR-dependent cell growth signaling and a clinically effective therapeutic target in mantle cell lymphoma (MCL). The molecular impact of BTK inhibition remains unclear particularly in hematopoietic malignancies. We analyzed the molecular mechanisms of BTK inhibition with the novel inhibitor BGB-3111 (zanubrutinib) in MCL models. The efficacy of BGB-3111 was investigated using growth proliferation/cell viability and apoptosis assays in MCL cell lines and patient-derived xenograft (PDX) MCL cells. The activity and mechanisms of BGB-3111 were further confirmed using a cell line xenograft model, an MCL PDX mouse model, and a human phosphokinase profiler array and reverse phase protein array. Finally, the mechanisms related to resistance to BTK inhibition were analyzed by creating cell lines with low levels of BTK using CRISPR/Cas 9 genome editing. We found that inhibition of BTK leads to suppression of tumor growth, which was mediated via potent suppression of AKT/mTOR, apoptosis, and metabolic stress. Moreover, targeted disruption of the BTK gene in MCL cells resulted in resistance to BTK inhibition and the emergence of novel survival mechanisms. Our studies suggest a general efficacy of BTK inhibition in MCL and potential drug resistance mechanism via alternative signaling pathways.

Original languageEnglish (US)
Pages (from-to)267-277
Number of pages11
JournalMolecular cancer therapeutics
Volume18
Issue number2
DOIs
StatePublished - Feb 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Bioinformatics Shared Resource
  • Flow Cytometry and Cellular Imaging Facility
  • Functional Proteomics Reverse Phase Protein Array Core
  • Research Animal Support Facility
  • Tissue Biospecimen and Pathology Resource
  • Cytogenetics and Cell Authentication Core

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