TY - JOUR
T1 - Pleiotropic action of novel Bruton's tyrosine kinase inhibitor BGB-3111 in mantle cell lymphoma
AU - Li, Carrie J.
AU - Jiang, Changying
AU - Liu, Yang
AU - Bell, Taylor
AU - Ma, Wencai
AU - Ye, Yin
AU - Huang, Shengjian
AU - Guo, Hui
AU - Zhang, Hui
AU - Wang, Lai
AU - Wang, Jing
AU - Nomie, Krystle
AU - Zhang, Liang
AU - Wang, Michael
N1 - Funding Information:
This study was supported by the NIH-funded Cancer Center Support Grant (CCSG) P30 CA016672 and the R21 CA202104 (to M. Wang, PI). This study was also partially supported by the generous philanthropic support to the MD Anderson B Cell Lymphoma Moon Shot Project and philanthropy funds from The Gary Rogers Foundation and the Kinder Foundation. The reagent BGB-3111 was provided by BeiGene. Cell line authentication was performed by the MD Anderson Cancer Center Characterized Cell Line Core Facility, funded by grant NCI No. CA016672.
Funding Information:
Michael Wang reports receiving commercial research grant from Janssen, Pharmacyclics, AstraZeneca, Kite Pharma, BeiGene, Novartis, and Celgene; also received other commercial research support from AstraZeneca; and is a consultant/advisory board member of Janssen, AstraZeneca, and MoreHealth. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059588413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059588413&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-18-0478
DO - 10.1158/1535-7163.MCT-18-0478
M3 - Article
C2 - 30413649
AN - SCOPUS:85059588413
SN - 1535-7163
VL - 18
SP - 267
EP - 277
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -