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Mol Cancer Ther. 2019 Feb;18(2):267-277. doi: 10.1158/1535-7163.MCT-18-0478. Epub 2018 Nov 9.

Pleiotropic Action of Novel Bruton's Tyrosine Kinase Inhibitor BGB-3111 in Mantle Cell Lymphoma.

Author information

1
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
4
BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhong-Guan-Cun Life Science Park, Changping District, Beijing, PR China.
5
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas. miwang@mdanderson.org.
6
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas.
#
Contributed equally

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.

PMID:
30413649
PMCID:
PMC6363842
[Available on 2020-02-01]
DOI:
10.1158/1535-7163.MCT-18-0478

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