American Association for Cancer Research
10780432ccr170650-sup-180051_2_supp_4089020_hr8qxt.pdf (131.65 kB)

Supplementary Figures from Combined BTK and PI3Kδ Inhibition with Acalabrutinib and ACP-319 Improves Survival and Tumor Control in CLL Mouse Model

Download (131.65 kB)
journal contribution
posted on 2023-03-31, 20:08 authored by Carsten U. Niemann, Helena I. Mora-Jensen, Eman L. Dadashian, Fanny Krantz, Todd Covey, Shih-Shih Chen, Nicholas Chiorazzi, Raquel Izumi, Roger Ulrich, Brian J. Lannutti, Adrian Wiestner, Sarah E.M. Herman

Supplementary Figures 1-4


National Heart, Lung, and Blood Institute

National Institutes of Health

Danish Cancer Society

Novo Nordisk



Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3Kδ and BTK inhibitors.Experimental Design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 in vivo. We compared single-agent with combination therapy in TCL1-192 cell–injected mice, a model of aggressive CLL.Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. Although single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over 2 weeks compared with either single agent. The combination reduced tumor proliferation, NF-κB signaling, and expression of BCL-xL and MCL-1 more potently than single-agent therapy.Conclusions: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies. Clin Cancer Res; 23(19); 5814–23. ©2017 AACR.