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Leukemia. 2019 Aug 30. doi: 10.1038/s41375-019-0569-7. [Epub ahead of print]

An in vitro assay for biomarker discovery and dose prediction applied to ibrutinib plus venetoclax treatment of CLL.

Author information

1
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. sigrid.skanland@medisin.uio.no.
2
K. G. Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. sigrid.skanland@medisin.uio.no.
3
K. G. Jebsen Centre for B cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. sigrid.skanland@medisin.uio.no.
4
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway. sigrid.skanland@medisin.uio.no.
5
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
6
K. G. Jebsen Centre for B cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
7
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway.
8
Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Oslo, Norway.
9
K. G. Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
10
Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.
11
Department of Haematology, Oslo University Hospital, Oslo, Norway.

Abstract

Recently, several small molecule drugs were approved for treatment of chronic lymphocytic leukemia (CLL), significantly improving patient management. However, knowledge about how to combine these therapies for optimal effects and what patients will best benefit from them is lacking. Here, we show that drug synergies can be identified by single cell signaling analyses. We investigated the effects of idelalisib, ibrutinib, and venetoclax on 35 protein epitopes by phospho flow in CLL cells. The activity of proteins in the B-cell receptor signalosome and the phosphatidylinositol 3-kinase pathway were altered upon drug exposure. Combined treatment with ibrutinib and venetoclax give promising results in clinical studies and we show that this combination exerted synergistic inhibitory effects on cell signaling and cell viability. Cell viability was monitored by flow cytometry and with independent drug sensitivity screens. Our analyses indicate that the standard dosages of ibrutinib and venetoclax can be lowered without loss of efficacy, potentially reducing drug costs, and toxicities. Observed correlation between signaling and viability indicates that signaling molecules could serve as biomarkers to predict response to therapy. We suggest that phospho flow should be considered as a novel approach for dose and synergy prediction in a precision medicine setting for CLL.

PMID:
31471562
DOI:
10.1038/s41375-019-0569-7

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