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 language | English |
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Pages (from-to) | 2367-2375 |
Number of pages | 9 |
Journal | Cell Cycle |
Volume | 14 |
Issue number | 14 |
Early online date | 7 Jan 2015 |
DOIs | |
Publication status | Published - 18 Jul 2015 |
Keywords
- myeloma
- bruton's tyrosine kinase
- NF-kappa B
- bortezomib
- ibrutinib
Profiles
-
Kristian Bowles
- Norwich Medical School - Dean of Norwich Medical School
- Cancer Studies - Member
Person: Research Group Member, Academic, Teaching & Research
-
Stuart Rushworth
- Norwich Medical School - Professor
- Metabolic Health - Director
- Cancer Studies - Member
Person: Research Group Member, Academic, Teaching & Research