Responses to the selective bruton's tyrosine kinase (btk) inhibitor tirabrutinib (ono/gs-4059) in diffuse large b-cell lymphoma cell lines

  • 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.

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Author:Ryohei Kozaki, Meike Vogler, Harriet S. Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J. S. Dyer, Toshio Yoshizawa
Pubmed Id:
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/04/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/11/11
Tag:BCR signaling; BTK; DLBCL; combination therapy
Issue:4, Art. 127
Page Number:11
First Page:1
Last Page:11
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0