title: Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma.
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.
authors.affiliation: a Department of Molecular Haematology; Norwich Medical School ; University of East Anglia ; Norwich , UK.
authors.forename: Megan Y
authors.initials: MY
authors.lastname: Murray
authors.forename: Lyubov
authors.initials: L
authors.lastname: Zaitseva
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Auger
authors.forename: Jenny Io
authors.initials: JI
authors.lastname: Craig
authors.forename: David J
authors.initials: DJ
authors.lastname: MacEwan
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000069286:Bortezomib / Q000627:therapeutic use / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D061988:Proteasome Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D035683:MicroRNAs; D010880:Piperidines; D061988:Proteasome Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D051996:Transcription Factor RelA; C551803:ibrutinib; D000069286:Bortezomib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine
keywords: BMSC – bone marrow stromal cells; BTK; BTK – Bruton's tyrosine kinase.; MM – multiple myeloma; NF-κB; NF-κB – nuclear factor-kappa B; PI – proteasome inhibitor; bortezomib; drug-resistance; ibrutinib; multiple myeloma