Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma.
Biochim Biophys Acta Mol Basis Dis
; 1865(6): 1666-1676, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-30954557
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.
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Base de dados:
MEDLINE
Assunto principal:
Resistencia a Medicamentos Antineoplásicos
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Inibidores de Proteassoma
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Modelos Biológicos
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Mutação
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article