Journal article
Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model
Molecular cancer therapeutics, Vol.12(6), pp.1140-1150
06/2013
DOI: 10.1158/1535-7163.MCT-12-1151
PMCID: PMC4076840
PMID: 23536725
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-X
L
/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.
Details
- Title: Subtitle
- Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model
- Creators
- Holly A.F Stessman - Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MinnesotaLinda B Baughn - Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MinnesotaAaron Sarver - Masonic Cancer Center Bioinformatics Support and Services, University of Minnesota, Minneapolis, MinnesotaTian Xia - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MinnesotaRaamesh Deshpande - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MinnesotaAatif Mansoor - Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MinnesotaSusan A Walsh - Department of Radiology, University of Iowa, Iowa City, IowaJohn J Sunderland - Department of Radiology, University of Iowa, Iowa City, IowaNathan G Dolloff - Department of Medicine, Penn State Hershey Medical Center, Hershey, PennsylvaniaMichael A Linden - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MinnesotaFenghuang Zhan - Department of Internal Medicine, University of Iowa, Iowa City, IowaSiegfried Janz - Department of Pathology, University of Iowa, Iowa City, IowaChad L Myers - Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MinnesotaBrian G Van Ness - Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.12(6), pp.1140-1150
- DOI
- 10.1158/1535-7163.MCT-12-1151
- PMID
- 23536725
- PMCID
- PMC4076840
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Language
- English
- Date published
- 06/2013
- Academic Unit
- Radiology; Pathology; Physics and Astronomy; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984046832602771
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