2. Academic Validation
  3. Responses to the Selective Bruton's Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines

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

  • Cancers (Basel). 2018 Apr 23;10(4):127. doi: 10.3390/cancers10040127.
Ryohei Kozaki 1 2,  Meike Vogler 3 4,  Harriet S Walter 5,  Sandrine Jayne 6,  David Dinsdale 7,  Reiner Siebert 8 9,  Martin J S Dyer 10 11,  Toshio Yoshizawa 12
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK. [email protected].
  • 2 Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan. [email protected].
  • 3 Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK. [email protected].
  • 4 Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, 60528 Frankfurt, Germany. [email protected].
  • 5 Ernest and Helen Scott Haematological Research Institute and Department of Cancer Studies, University of Leicester, Leicester LE1 7RH, UK. [email protected].
  • 6 Ernest and Helen Scott Haematological Research Institute and Department of Cancer Studies, University of Leicester, Leicester LE1 7RH, UK. [email protected].
  • 7 MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK. [email protected].
  • 8 Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, D-24105 Kiel, Germany. [email protected].
  • 9 Institute for Human Genetics, Ulm University, D-89081 Ulm, Germany. [email protected].
  • 10 Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK. [email protected].
  • 11 Ernest and Helen Scott Haematological Research Institute and Department of Cancer Studies, University of Leicester, Leicester LE1 7RH, UK. [email protected].
  • 12 Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan. [email protected].
PMID: 29690649 DOI: 10.3390/cancers10040127
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

BCR signaling; BTK; DLBCL; combination therapy.

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