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

Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1666-1676. doi: 10.1016/j.bbadis.2019.04.003. Epub 2019 Apr 4.

Abstract

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.

Keywords: Ixazomib resistance; Multiple myeloma; PSMB5 mutation; Proteasome inhibitor resistance; Protein homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Amino Acid Substitution
  • Antineoplastic Agents / pharmacology*
  • Boron Compounds / pharmacology
  • Bortezomib / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Indoles / pharmacology
  • Models, Biological*
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Mutation*
  • Oligopeptides / pharmacology
  • Panobinostat / pharmacology
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology*
  • Pyrimidines / pharmacology
  • Thiazoles / pharmacology

Substances

  • Antineoplastic Agents
  • Boron Compounds
  • CB-5083
  • Indoles
  • Oligopeptides
  • Proteasome Inhibitors
  • Pyrimidines
  • Thiazoles
  • Alpelisib
  • Bortezomib
  • ixazomib
  • carfilzomib
  • Panobinostat
  • Phosphatidylinositol 3-Kinase
  • PSMB1 protein, human
  • PSMB5 protein, human
  • Proteasome Endopeptidase Complex
  • Histone Deacetylases
  • Glycine