A clinically relevant pulse treatment generates a bortezomib-resistant myeloma cell line that lacks proteasome mutations and is sensitive to Bcl-2 inhibitor venetoclax.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/therapeutic use ; Multiple Myeloma*/drug therapy ; Multiple Myeloma*/genetics; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Humans ; Mutation ; Neoplasm Recurrence, Local ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/pharmacology ; Sulfonamides

Proteasome inhibitors bortezomib and carfilzomib are the backbones of treatments of multiple myeloma, which remains incurable despite many recent advances. With many patients relapsing despite high initial response rates to proteasome inhibitor-containing regimens, it is critical to understand the process of acquired resistance. In vitro generated resistant cell lines are important tools in this process. The majority of previously developed bortezomib-resistant cell lines bear mutations in the proteasome PSMB5 sites, the prime target of bortezomib and carfilzomib, which are rarely observed in patients. Here we present a novel bortezomib-resistant derivative of the KMS-12-BM multiple myeloma cell line, KMS-12-BM-BPR. Unlike previously published bortezomib-resistant cell lines, it was created using clinically relevant twice-weekly pulse treatments with bortezomib instead of continuous incubation. It does not contain mutations in the PSMB5 site and retains its sensitivity to carfilzomib. Reduced load on proteasome due to decreased protein synthesis appears to be the main cause of resistance. In addition, KMS-12-BM-BPR cells are more sensitive to Bcl-2 inhibitor venetoclax. Overall, this study demonstrates the feasibility of creating a proteasome inhibitor resistant myeloma cell lines by using clinically relevant pulse treatments and provides a novel model of acquired resistance.
(© 2022. The Author(s).)

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R01 CA213223 United States CA NCI NIH HHS; 5R01CA213223 United States CA NCI NIH HHS; 5P30 CA023108-41 United States CA NCI NIH HHS

0 (Antineoplastic Agents)
0 (Bridged Bicyclo Compounds, Heterocyclic)
0 (Proteasome Inhibitors)
0 (Sulfonamides)
69G8BD63PP (Bortezomib)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
N54AIC43PW (venetoclax)

Date Created: 20220727 Date Completed: 20220729 Latest Revision: 20231204

20231204

PMC9329464

10.1038/s41598-022-17239-3

35896610