title: Sequence analysis of β-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone.
abstract: Variations within proteasome β (PSMB) genes, which encode the β subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib and/or long-term outcomes, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity.
authors.affiliation: Millennium Pharmaceuticals, 35 Landsdowne St, Cambridge, MA 02139, USA. david.lichter@MPI.com
authors.forename: David I
authors.initials: DI
authors.lastname: Lichter
authors.forename: Hadi
authors.initials: H
authors.lastname: Danaee
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pickard
authors.forename: Olga
authors.initials: O
authors.lastname: Tayber
authors.forename: Michael
authors.initials: M
authors.lastname: Sintchak
authors.forename: Hongliang
authors.initials: H
authors.lastname: Shi
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.forename: Joan
authors.initials: J
authors.lastname: Bladé
authors.forename: Thierry
authors.initials: T
authors.lastname: Façon
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.forename: William
authors.initials: W
authors.lastname: Dalton
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Deborah
authors.initials: D
authors.lastname: Ricci
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: William L
authors.initials: WL
authors.lastname: Trepicchio
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D003907:Dexamethasone / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D011719:Pyrazines / Q000627:therapeutic use*; D012008:Recurrence; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D021122:Protein Subunits; D011719:Pyrazines; C071313:LMP-2 protein; D000069286:Bortezomib; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C577981:PSMB1 protein, human; C098948:PSMB10 protein, human; C088874:PSMB5 protein, human; C088875:PSMB6 protein, human; D046988:Proteasome Endopeptidase Complex