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


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.
FachzeitschriftInternational Journal of Molecular Sciences
PublikationsstatusVeröffentlicht - 1 Dez 2021

ASJC Scopus subject areas

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


Untersuchen Sie die Forschungsthemen von „BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells“. Zusammen bilden sie einen einzigartigen Fingerprint.

Dieses zitieren