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

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.

A multicenter, open‐label, phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

“…Tirabrutinib (ONO/GS-4059) is a highly potent and selective second-generation BTK inhibitor. 27,28 Tirabrutinib forms a covalent bond with BTK and has demonstrated effective in vitro cytotoxicity in B-cell lymphoma and in vivo antitumor activity in mouse models. 27 Multicenter, dose-escalation phase I trials of tirabrutinib for relapsed or refractory CLL and B-cell lymphoma, including WM, have demonstrated the efficacy and tolerability of tirabrutinib.…”

“…27,28 Tirabrutinib forms a covalent bond with BTK and has demonstrated effective in vitro cytotoxicity in B-cell lymphoma and in vivo antitumor activity in mouse models. 27 Multicenter, dose-escalation phase I trials of tirabrutinib for relapsed or refractory CLL and B-cell lymphoma, including WM, have demonstrated the efficacy and tolerability of tirabrutinib. 29,30 Therefore, we conducted a multicenter, open-label, phase II study of tirabrutinib to evaluate its efficacy and safety in patients with WM.…”

Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption

“…Tirabrutinib inhibits cell proliferation in some malignant B-cell lines but does not inhibit the activation of T-lymphocytes from human PBMCs (Kozaki et al, 2018). …”

Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia

“…Cells were treated with venetoclax, 9 A1331852, 10 and S63845 11 (Selleck Chemicals, Houston, TX) for 24 hours before analysis using CellTiter-Glo. 12…”