Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

Megan Y. Murray, Lyubov Zaitseva, Martin J. Auger, Jenny I.O. Craig, David MacEwan, Stuart A. Rushworth, Kristian M. Bowles (Lead Author)

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Abstract

Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10-15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n = 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n = 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 μM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-κB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-κB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-κB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 ± 6 .9 %, ANOVA P ≤ 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib.
Original languageEnglish
Pages (from-to)2367-2375
Number of pages9
JournalCell Cycle
Volume14
Issue number14
Early online date7 Jan 2015
DOIs
Publication statusPublished - 18 Jul 2015

Keywords

  • myeloma
  • bruton's tyrosine kinase
  • NF-kappa B
  • bortezomib
  • ibrutinib

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