Next Article in Journal
Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes?
Next Article in Special Issue
Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response
Previous Article in Journal
Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress
Previous Article in Special Issue
The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 10
Issue 4
10.3390/cancers10040127
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines

by
Ryohei Kozaki
1,2,†,
Meike Vogler
1,3,†,
Harriet S. Walter
4,
Sandrine Jayne
4,
David Dinsdale
5,
Reiner Siebert
6,7,8,
Martin J.S. Dyer
1,4 and
Toshio Yoshizawa
2,*
1
Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK
2
Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan
3
Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, 60528 Frankfurt, Germany
4
Ernest and Helen Scott Haematological Research Institute and Department of Cancer Studies, University of Leicester, Leicester LE1 7RH, UK
5
MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK
6
Institute for Human Genetics, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
7
Institute for Human Genetics, Ulm University, D-89081 Ulm, Germany
8
University Hospital Schleswig Holstein, D-24105 Kiel, Germany
*
Author to whom correspondence should be addressed.
†
The authors contributed equally to this work.
Cancers 2018, 10(4), 127; https://doi.org/10.3390/cancers10040127
Submission received: 15 March 2018 / Revised: 13 April 2018 / Accepted: 20 April 2018 / Published: 23 April 2018
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
Browse Figures
Versions Notes

Abstract

Bruton’s tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL.
Keywords: DLBCL; BCR signaling; BTK; combination therapy DLBCL; BCR signaling; BTK; combination therapy

Share and Cite

MDPI and ACS Style

Kozaki, R.; Vogler, M.; Walter, H.S.; Jayne, S.; Dinsdale, D.; Siebert, R.; Dyer, M.J.S.; Yoshizawa, T. Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines. Cancers 2018, 10, 127. https://doi.org/10.3390/cancers10040127

AMA Style

Kozaki R, Vogler M, Walter HS, Jayne S, Dinsdale D, Siebert R, Dyer MJS, Yoshizawa T. Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines. Cancers. 2018; 10(4):127. https://doi.org/10.3390/cancers10040127

Chicago/Turabian Style

Kozaki, Ryohei, Meike Vogler, Harriet S. Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J.S. Dyer, and Toshio Yoshizawa. 2018. "Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines" Cancers 10, no. 4: 127. https://doi.org/10.3390/cancers10040127

APA Style

Kozaki, R., Vogler, M., Walter, H. S., Jayne, S., Dinsdale, D., Siebert, R., Dyer, M. J. S., & Yoshizawa, T. (2018). Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines. Cancers, 10(4), 127. https://doi.org/10.3390/cancers10040127

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop