Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-tomicroenvironment 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 TP53mutclones during 12 months of treatment. In parallel, the antileukemic activity of Ibrutinib was assessed in vitro on B-CLL patient cell cultures in combination with ?-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.

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

Secchiero, Paola
Co-primo
;
Voltan, Rebecca
Co-primo
;
Rimondi, Erika;Melloni, Elisabetta;Tisato, Veronica;Gallo, Stefania;Rigolin, Gian Matteo
Penultimo
;
Zauli, Giorgio
Ultimo
2017

Abstract

Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-tomicroenvironment 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 TP53mutclones during 12 months of treatment. In parallel, the antileukemic activity of Ibrutinib was assessed in vitro on B-CLL patient cell cultures in combination with ?-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.
Secchiero, Paola; Voltan, Rebecca; Rimondi, Erika; Melloni, Elisabetta; Athanasakis, Emmanouil; Tisato, Veronica; Gallo, Stefania; Rigolin, Gian Matteo; Zauli, Giorgio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2381349
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