title: Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model.
abstract: Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Holly A F
authors.initials: HA
authors.lastname: Stessman
authors.forename: Linda B
authors.initials: LB
authors.lastname: Baughn
authors.forename: Aaron
authors.initials: A
authors.lastname: Sarver
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.forename: Raamesh
authors.initials: R
authors.lastname: Deshpande
authors.forename: Aatif
authors.initials: A
authors.lastname: Mansoor
authors.forename: Susan A
authors.initials: SA
authors.lastname: Walsh
authors.forename: John J
authors.initials: JJ
authors.lastname: Sunderland
authors.forename: Nathan G
authors.initials: NG
authors.lastname: Dolloff
authors.forename: Michael A
authors.initials: MA
authors.lastname: Linden
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.forename: Chad L
authors.initials: CL
authors.lastname: Myers
authors.forename: Brian G
authors.initials: BG
authors.lastname: Van Ness
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage*; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: C494812:Bcl2l1 protein, mouse; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D011719:Pyrazines; D051020:bcl-X Protein; D000069286:Bortezomib; D006655:Histone Deacetylases
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