Faculty Collaboration Database

Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther 2013 Jun;12(6):1140-50

Date

03/29/2013

Pubmed ID

23536725

Pubmed Central ID

PMC4076840

DOI

10.1158/1535-7163.MCT-12-1151

Scopus ID

2-s2.0-84879293601 (requires institutional sign-in at Scopus site)   62 Citations

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.

Author List

Stessman HA, Baughn LB, Sarver A, Xia T, Deshpande R, Mansoor A, Walsh SA, Sunderland JJ, Dolloff NG, Linden MA, Zhan F, Janz S, Myers CL, Van Ness BG

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Boronic Acids
Bortezomib
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes, myc
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Mice
Mice, Transgenic
Multiple Myeloma
Pyrazines
bcl-X Protein