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

The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells.
Oncotarget. 2017 Jul 22;:
Authors: Secchiero P, Voltan R, Rimondi E, Melloni E, Athanasakis E, Tisato V, Gallo S, Matteo Rigolin G, Zauli G
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...

Source: Oncotarget - August 7, 2017 Category: Cancer & Oncology Tags: Oncotarget Source Type: research