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

Paola Secchiero, Rebecca Voltan, Erika Rimondi, Elisabetta Melloni, Emmanouil Athanasakis, Veronica Tisato, Stefania Gallo, Gian Matteo Rigolin, Giorgio Zauli

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)59235-59245
Number of pages11
JournalOncotarget
Volume8
Issue number35
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • B-leukemic cells
  • Combination therapy
  • Ibrutinib
  • NOTCH1
  • γ-secretase inhibitors

ASJC Scopus subject areas

  • Oncology

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