Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach

Sina Sender, Ahmad Wael Sultan, Daniel Palmer, Dirk Koczan, Anett Sekora, Julia Beck, Ekkehard Schuetz, Leila Taher, Bertram Brenig, Georg Fuellen, Christian Junghanss, Hugo Murua Escobar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Both bromodomain and extra-terminal domain (BET) proteins and spleen tyrosine kinase (SYK) represent promising targets in diffuse large B-cell (DLBCL) and Burkitt's lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. Methods: The effect of the single agents on cell proliferation and metabolic activity was evaluated in two DLBCL and two BL cell lines. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were further investigated after a combined treatment of AZD or I-BET and Ento. RNAseq profiling of combined AZD+Ento treatment was performed in SU-DHL-4 cells. Results: Both BET inhibitors reduced cell proliferation and metabolic activity in a dose- and time-dependent manner. Combined BET and SYK inhibition enhanced the anti-proliferative effect and induced a G0/G1 cell cycle arrest. SU-DHL-4 demonstrated a pronounced modulation of gene expression by AZD, which was markedly increased by additional SYK inhibition. Functional enrichment analyses identified combination-specific GO terms related to DNA replication and cell division. Genes such as ADGRA2, MYB, TNFRSF11A, S100A10, PLEKHH3, DHRS2 and FOXP1-AS1 were identified as possible key regulators. Conclusion: Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature.

Original languageEnglish
Article number4691
JournalCancers
Volume14
Issue number19
DOIs
Publication statusPublished - Oct 2022

Keywords

  • AZD5153
  • BET
  • BL
  • DLBCL
  • drug combination
  • entospletinib
  • gene expression
  • I-BET151
  • lymphoma
  • SYK

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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