Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma |
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Authors: | Megan Y Murray Lyubov Zaitseva Martin J Auger Jenny IO Craig David J MacEwan Stuart A Rushworth Kristian M Bowles |
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Institution: | 1.Department of Molecular Haematology; Norwich Medical School; University of East Anglia; Norwich, UK;2.Department of Haematology; Norfolk and Norwich University Hospitals NHS Foundation Trust; Norwich, UK;3.Department of Haematology; Addenbrooke''s Hospital; Cambridge Institute for Medical Research; Cambridge, UK;4.Department of Molecular and Clinical Pharmacology; Institute of Translational Medicine; University of Liverpool; Liverpool, UK.;†SAR and KMB contributed equally. |
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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. |
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Keywords: | BTK bortezomib drug-resistance ibrutinib multiple myeloma NF-κ B |
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