BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells

Weibo Kong, Sina Sender, Leila Taher, Simon Villa-Perez, Yixuan Ma, Anett Sekora, Barbara C. Ruetgen, Bertram Brenig, Julia Beck, Ekkehard Schuetz, Christian Junghanss, Ingo Nolte, Hugo Murua Escobar

Publikation: Beitrag in einer FachzeitschriftArtikelBegutachtung

Abstract

Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the single and combined application of the BTK inhibitor ibrutinib and the selective PI3Kγ inhibitor AS-605240 in the canine DLBCL cell line CLBL-1. For further comparison, key findings were additionally analyzed in canine B-cell leukemia GL-1 and human DLBCL cell line SU-DHL-4. While ibrutinib alone induced significant anti-proliferative effects on all cell lines in a dose-dependent manner, AS-605240 only induced anti-proliferative effects at high concentrations. Interestingly, ibrutinib and AS-605240 acted synergistically, reducing cell proliferation and increasing apoptosis/necrosis in all cell lines and inducing morphological changes in CLBL-1. Moreover, the combined application of ibrutinib and AS-605240 reduced relative phosphorylation and, in some instances, the levels of the BTK, AKT, GSK3β, and ERK proteins. Comparative variant analysis of RNA-seq data among canine B- and T-lymphoid cell lines and primary B-cell lymphoma samples revealed potentially high-impact somatic variants in the genes that encode PI3K, which may explain why AS-605240 does not singly inhibit the proliferation of cell lines. The combination of ibrutinib and AS-605240 represents a promising approach that warrants further in vivo evaluation in dogs, potentially bearing significant value for the treatment of human DLBCL.
Originalspracheenglisch
Aufsatznummer12673
FachzeitschriftInternational Journal of Molecular Sciences
Jahrgang22
Ausgabenummer23
DOIs
PublikationsstatusVeröffentlicht - 1 Dez 2021

ASJC Scopus subject areas

  • Molekularbiologie
  • Spektroskopie
  • Katalyse
  • Anorganische Chemie
  • Angewandte Informatik
  • Physikalische und Theoretische Chemie
  • Organische Chemie

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