Journal
CELL CYCLE
Volume 14, Issue 14, Pages 2367-2375Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2014.998067
Keywords
BTK; bortezomib; drug-resistance; ibrutinib; multiple myeloma; NF-kappa B
Categories
Funding
- NIHR
- Big C Appeal, Worldwide Cancer Research
- Humane Research Trust
- Worldwide Cancer Research [12-0014] Funding Source: researchfish
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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 (0.5M) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5nM). Further analysis of pro-survival signaling revealed a role for the NF-B p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-B p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-B 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.
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