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


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 ?-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.

SUBMITTER: Secchiero P 

PROVIDER: S-EPMC5601728 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Secchiero Paola P   Voltan Rebecca R   Rimondi Erika E   Melloni Elisabetta E   Athanasakis Emmanouil E   Tisato Veronica V   Gallo Stefania S   Rigolin Gian Matteo GM   Zauli Giorgio G  

Oncotarget 20170722 35


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 <i>TP53</i> mutations, the frequency of the mutated clones was monitor  ...[more]

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