@article{10902/23829,
year = {2021},
url = {http://hdl.handle.net/10902/23829},
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.},
organization = {Funding: This work was supported by funds from the Spanish ISCIII-FIS and FEDER (PI15/02156, PI15/00067, PI18/00591, PI18/01600, and PI19/01384), the Network of Regenerative Medicine and Cellular Therapy of Castilla y León, the Regional Health Council of Castilla y León (GRS 1604/A/17), and the AECC (PROYE20047GUTI). E.M.A. was supported by a predoctoral research contract from the Regional Education Council of Junta Castilla y León (JCyL) co-financed by the European Social Fund. T.P. is supported by a grant from the AECC (INVES18043PAÍN).},
publisher = {MDPI},
publisher = {Cells
. 2021 Mar 4;10(3):559},
title = {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},
author = {Algarín, Esperanza M. and Quwaider, Dalia and Campos-Laborie, Francisco J. and Díaz-Tejedor, Andrea and Mogollón, Pedro and Vuelta, Elena and Martín-Sánchez, Montserrat and San-Segundo, Laura and González-Méndez, Lorena and Gutiérrez, Norma C. and García-Sanz, Ramón and Paíno, Teresa and Rivas, Javier De Las and Ocio San Miguel, Enrique María and Garayoa, Mercedes},
}