TY  - JOUR
A1  - Kozaki, Ryohei
A1  - Vogler, Meike
A1  - Walter, Harriet S.
A1  - Jayne, Sandrine
A1  - Dinsdale, David
A1  - Siebert, Reiner
A1  - Dyer, Martin J. S.
A1  - Yoshizawa, Toshio
T1  - Responses to the selective bruton's tyrosine kinase (btk) inhibitor tirabrutinib (ono/gs-4059) in diffuse large b-cell lymphoma cell lines
T2  - Cancers
N2  - 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.
KW  - DLBCL
KW  - BCR signaling
KW  - BTK
KW  - combination therapy
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51481
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-514812
SN  - 2072-6694
N1  - 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
VL  - 10
IS  - 4, Art. 127
SP  - 1
EP  - 11
PB  - MDPI
CY  - Basel
ER  -