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Title: The BET bromodomain inhibitor CPI203 improves lenalidomide activity in in vitro and in vivo models of multiple myeloma by synergistic blockade of Ikaros and Myc signaling.
Author: Díaz Sánchez, Tania
Rodríguez, Vanina
Lozano, Ester
Mena Jaramillo, Mari Pau
Calderón, Marcos
Rosiñol Dachs, Laura
Martínez, Antonio
Tovar, Natalia
Pérez Galán, Patricia
Bladé, J. (Joan)
Roué, Gaël
Fernández de Larrea Rodríguez, Carlos José
Keywords: Mieloma múltiple
Multiple myeloma
Issue Date: Oct-2017
Publisher: Ferrata Storti Foundation
Abstract: Most patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinational effect of an MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of the BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5 μM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with the mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (P=0.04). Finally, in a SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even in cases with suboptimal prior response to immunomodulatory drugs.
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It is part of: Haematologica, 2017, vol. 102, num. 10, p. 1776-1784
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ISSN: 0390-6078
Appears in Collections:Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques)

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