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

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

doi:10.18632/oncotarget.19494

Paola Secchiero, Emmanouil Athanasakis + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.19494

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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 the NOTCH1 and c-MYC pathways, warrants further experimentation for its potential therapeutic applications.

Highlights

The therapy of B chronic lymphocytic leukemia (B-CLL) is rapidly evolving, as inhibitors of B-cell receptor (BCR) signaling have shown substantial activity in the absence of traditional immune-chemotherapy [1, 2]
Among the B-CLL population analyzed, all characterized for having unmutated Bruton tyrosine kinase (BTK) and PLCγ2, six patients underwent to Ibrutinib therapy and three of them carried TP53 functional mutations, in different genetic sites and at different clonal frequency (Table 1 and Figure 1)
Similar trend was observed in Pt.#2 and in Pt.#4 after 12 months of Ibrutinib therapy (Figure 1). These findings reinforce the notion of the efficacy of Ibrutinib in B-CLL carrying TP53 mutations [18, 19], and provide the first evidence concerning the ability of Ibrutinib to target the TP53mut clones

Summary

Introduction

The therapy of B chronic lymphocytic leukemia (B-CLL) is rapidly evolving, as inhibitors of B-cell receptor (BCR) signaling have shown substantial activity in the absence of traditional immune-chemotherapy [1, 2]. The vast majority of B-CLL patients treated with Ibrutinib shows evident clinical benefit [4,5,6,7], some B-CLL patients develop progressive disease after prolonged treatment. Such secondary resistance to Ibrutinib has been associated, in some cases, with acquired mutations in either BTK or in www.impactjournals.com/oncotarget its downstream target PLCγ [8, 9]. Regardless of the mutational status, the activation of NOTCH1 signaling, through interactions with its surface ligands, might render B-CLL cells more resistant to spontaneous and chemotherapy-induced apoptosis [13,14,15]. The binding to NOTCH1 ligands, belonging to the Jagged or Delta-like ligand (DLL) families, triggers multiple proteolytic cleavages of the NOTCH1 protein, the last of which is operated by the γ-secretase enzyme, causing nuclear translocation of the intra-cellular domain of NOTCH1 (ICN) [16, 17]

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