Oncotarget

Research Papers:

The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells

Paola Secchiero, Rebecca Voltan, Erika Rimondi, Elisabetta Melloni, Emmanouil Athanasakis, Veronica Tisato, Stefania Gallo, Gian Matteo Rigolin and Giorgio Zauli _

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Oncotarget. 2017; 8:59235-59245. https://doi.org/10.18632/oncotarget.19494

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Abstract

Paola Secchiero1,*, Rebecca Voltan1,*, Erika Rimondi1, Elisabetta Melloni1, Emmanouil Athanasakis2, Veronica Tisato1, Stefania Gallo1, Gian Matteo Rigolin3 and Giorgio Zauli1

1Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy

2Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy

3Department of Medical Sciences, Section of Hematology, University of Ferrara, Ferrara, Italy

*These authors have contributed equally to this work

Correspondence to:

Giorgio Zauli, email: [email protected]

Paola Secchiero, email: [email protected]

Keywords: B-leukemic cells, Ibrutinib, γ-secretase inhibitors, NOTCH1, combination therapy

Received: May 05, 2017    Accepted: June 20, 2017    Published: July 22, 2017

ABSTRACT

Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-to-microenvironment interactions. Ibrutinib plays a key role in the management of B-CLL and is recommended for first line treatment of high-risk CLL patients with 17p deletion. Therefore, elucidating the factors governing sensitivity/resistance to Ibrutinib represents a relevant issue. For this purpose, in 3 B-CLL patient samples harboring functional TP53 mutations, the frequency of the mutated clones was monitored during in vivo Ibrutinib therapy, revealing a progressive decline of the frequency of TP53mut clones during 12 months of treatment. In parallel, the anti-leukemic activity of Ibrutinib was assessed in vitro on B-CLL patient cell cultures in combination with γ-secretase inhibitors (GSI). In the in vitro assays, the combination of Ibrutinib+GSI exhibited enhanced cytotoxicity on B-CLL cells also in the presence of stroma and it was coupled to the down-regulation of the stroma-activated NOTCH1 and c-MYC pathways. Moreover, the combined treatment was effective in reducing CXCR4 expression and functions. Therefore, the ability of GSI to enhance the Ibrutinib anti-leukemic activity in B-CLL cells, by down-regulating the NOTCH1 and c-MYC pathways, warrants further experimentation for its potential therapeutic applications.


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