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EnglishIbrutinib 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.
| Data di pubblicazione: | 2017 | |
| Titolo: | The gamma-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells | |
| Autori: | Secchiero, Paola; Voltan, Rebecca; Rimondi, Erika; Melloni, Elisabetta; Athanasakis, Emmanouil; Tisato, Veronica; Gallo, Stefania; Rigolin, Gian Matteo; Zauli, Giorgio | |
| Rivista: | ONCOTARGET | |
| Keywords: | B-leukemic cells, Combination therapy, Ibrutinib, NOTCH1, γ-secretase inhibitors | |
| Abstract in inglese: | 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. | |
| Digital Object Identifier (DOI): | 10.18632/oncotarget.19494 | |
| Handle: | http://hdl.handle.net/11392/2381349 | |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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| Secchiero oncotarget 2017.pdf | Full text (versione editoriale) |  | Open Access Visualizza/Apri |
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