TY - JOUR
T1 - The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells
AU - Secchiero, Paola
AU - Voltan, Rebecca
AU - Rimondi, Erika
AU - Melloni, Elisabetta
AU - Athanasakis, Emmanouil
AU - Tisato, Veronica
AU - Gallo, Stefania
AU - Rigolin, Gian Matteo
AU - Zauli, Giorgio
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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 TP53mut clones 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.
AB - 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 TP53mut clones 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.
KW - B-leukemic cells
KW - Combination therapy
KW - Ibrutinib
KW - NOTCH1
KW - γ-secretase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85029082848&partnerID=8YFLogxK
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U2 - 10.18632/oncotarget.19494
DO - 10.18632/oncotarget.19494
M3 - Article
AN - SCOPUS:85029082848
VL - 8
SP - 59235
EP - 59245
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 35
ER -