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Stroma-Mediated Resistance to S63845 and Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Algarín, Esperanza M 
Quwaider, Dalia 
Campos-Laborie, Francisco J  ORCID logo  https://orcid.org/0000-0002-1213-0457
Díaz-Tejedor, Andrea  ORCID logo  https://orcid.org/0000-0003-0802-9767

Abstract

BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-XL. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM.

Description

Keywords

BH3-mimetics, anti-apoptotic proteins, mesenchymal stromal cells, miR-193, miR-21, multiple myeloma, Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Drug Resistance, Neoplasm, Humans, Multiple Myeloma, Proto-Oncogene Proteins c-bcl-2, Pyrimidines, Sulfonamides, Thiophenes

Journal Title

Cells

Conference Name

Journal ISSN

2073-4409
2073-4409

Volume Title

10

Publisher

MDPI AG