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

Journal Paper/Review - Apr 4, 2019

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Brünnert D, Kraus M, Stühmer T, Kirner S, Heiden R, Goyal P, Driessen C, Bargou R, Chatterjee M. Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1666-1676.
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Journal Paper/Review (English)
Journal
Biochim Biophys Acta Mol Basis Dis 2019; 1865
Publication Date
Apr 4, 2019
Issn Print
Issn Electronic
1879-260X
Pages
1666-1676
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Brief description/objective

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.