title: The novel β2-selective proteasome inhibitor LU-102 decreases phosphorylation of I kappa B and induces highly synergistic cytotoxicity in combination with ibrutinib in multiple myeloma cells.
abstract: OBJECTIVE
  Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (β1, β2, β5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting β5 subunit. It is unknown whether β2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IκB and activation of NF-κB in MM cells, while ibrutinib inhibits the IκB/NF-κB axis, suggesting antagonistic signaling. A β2-selective proteasome inhibitor may lack such antagonistic signaling effects.
  
  
  METHODS
  We recently introduced LU-102, the first β2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIκB/NF-κB signaling and their cytotoxic activity in combination with ibrutinib.
  
  
  RESULTS
  LU-102 reduced phosphorylation of IκB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-κB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib.
  
  
  CONCLUSIONS
  Ibrutinib is highly synergistic with β2-selective proteasome inhibition against MM and MCL in vitro. Novel β2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies.
authors.affiliation: Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kraus
authors.forename: Marianne
authors.initials: M
authors.lastname: Kraus
authors.forename: Nora
authors.initials: N
authors.lastname: Liu
authors.forename: Lenka
authors.initials: L
authors.lastname: Besse
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bader
authors.forename: Paul P
authors.initials: PP
authors.lastname: Geurink
authors.forename: Gerjan
authors.initials: G
authors.lastname: de Bruin
authors.forename: Alexei F
authors.initials: AF
authors.lastname: Kisselev
authors.forename: Herman
authors.initials: H
authors.lastname: Overkleeft
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy; D009101:Multiple Myeloma / Q000188:drug therapy*; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D020672:I-kappa B Proteins; D009842:Oligopeptides; D010880:Piperidines; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D011743:Pyrimidines; C000602005:azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone; C551803:ibrutinib; D000069286:Bortezomib; C524865:carfilzomib; D000225:Adenine