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Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma.
Journal article

Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma.

  • Brünnert D University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany. Electronic address: Bruennert_D@ukw.de.
  • Kraus M Kantonsspital St. Gallen, Clinic for Oncology/Hematology, St. Gallen, Switzerland.
  • Stühmer T University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany.
  • Kirner S University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany.
  • Heiden R University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany.
  • Goyal P Central University of Rajasthan, Department of Biotechnology, School of Life Sciences, Bandar Sindri, Kishangarh, India.
  • Driessen C Kantonsspital St. Gallen, Clinic for Oncology/Hematology, St. Gallen, Switzerland.
  • Bargou RC University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany.
  • Chatterjee M University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany.
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  • 2019-04-08
Published in:
  • Biochimica et biophysica acta. Molecular basis of disease. - 2019
Ixazomib resistance
Multiple myeloma
PSMB5 mutation
Proteasome inhibitor resistance
Protein homeostasis
A549 Cells
Amino Acid Substitution
Antineoplastic Agents
Boron Compounds
Bortezomib
Cell Line, Tumor
Cell Survival
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Gene Expression
Glycine
Histone Deacetylases
Humans
Indoles
Models, Biological
Multiple Myeloma
Mutation
Oligopeptides
Panobinostat
Phosphatidylinositol 3-Kinase
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Pyrimidines
Thiazoles
English Experimental data on resistance mechanisms of multiple myeloma (MM) to ixazomib (IXA), a second-generation proteasome inhibitor (PI), are currently lacking. We generated MM cell lines with a 10-fold higher resistance to IXA as their sensitive counterparts, and observed cross-resistance towards the PIs carfilzomib (CFZ) and bortezomib (BTZ). Analyses of the IXA-binding proteasome subunits PSMB5 and PSMB1 show increased PSMB5 expression and activity in all IXA-resistant MM cells, and upregulated PSMB1 expression in IXA-resistant AMO1 cells. In addition, sequence analysis of PSMB5 revealed a p.Thr21Ala mutation in IXA-resistant MM1.S cells, and a p.Ala50Val mutation in IXA-resistant L363 cells, whereas IXA-resistant AMO1 cells lack PSMB5 mutations. IXA-resistant cells retain their sensitivity to therapeutic agents that mediate cytotoxic effects via induction of proteotoxic stress. Induction of ER stress and apoptosis by the p97 inhibitor CB-5083 was strongly enhanced in combination with the PI3Kα inhibitor BYL-719 or the HDAC inhibitor panobinostat suggesting potential therapeutic strategies to circumvent IXA resistance in MM. Taken together, our newly established IXA-resistant cell lines provide first insights into resistance mechanisms and overcoming treatment strategies, and represent suitable models to further study IXA resistance in MM.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/126586
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