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

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-ap...

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Bibliographic Details
Authors: Algarín, Esperanza M., Quwaider, Dalia, Campos-Laborie, Francisco J., Díaz-Tejedor, Andrea, Mogollón, Pedro, Vuelta, Elena, Martín-Sánchez, Montserrat, San-Segundo, Laura, González-Méndez, Lorena, Gutiérrez, Norma C., García-Sanz, Ramón, Paíno, Teresa, Rivas, Javier De Las, Ocio San Miguel, Enrique María|||0000-0002-5765-0085, Garayoa, Mercedes
Format: article
Publication Date:2021
Country:España
Institution:Universidad de Cantabria (UC)
Repository:UCrea Repositorio Abierto de la Universidad de Cantabria
Language:English
OAI Identifier:oai:repositorio.unican.es:10902/23829
Online Access:http://hdl.handle.net/10902/23829
Access Level:Open access
Keyword:BH3-Mimetics
Anti-Apoptotic Proteins
Mesenchymal Stromal Cells
MiR-193
MiR-21
Multiple Myeloma
Description
Summary: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.

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