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The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling.
Haematologica. 2017 10; 102(10):1776-1784.H

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.

Authors+Show Affiliations

Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Hematopathology Unit, Department of Pathology, Hospital Clinic, IDIBAPS, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain cfernan1@clinic.ub.es groue@clinic.ub.es. Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain cfernan1@clinic.ub.es groue@clinic.ub.es. Division of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona, Spain.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28751557

Citation

Díaz, Tania, et al. "The BET Bromodomain Inhibitor CPI203 Improves Lenalidomide and Dexamethasone Activity in in Vitro and in Vivo Models of Multiple Myeloma By Blockade of Ikaros and MYC Signaling." Haematologica, vol. 102, no. 10, 2017, pp. 1776-1784.
Díaz T, Rodríguez V, Lozano E, et al. The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling. Haematologica. 2017;102(10):1776-1784.
Díaz, T., Rodríguez, V., Lozano, E., Mena, M. P., Calderón, M., Rosiñol, L., Martínez, A., Tovar, N., Pérez-Galán, P., Bladé, J., Roué, G., & de Larrea, C. F. (2017). The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling. Haematologica, 102(10), 1776-1784. https://doi.org/10.3324/haematol.2017.164632
Díaz T, et al. The BET Bromodomain Inhibitor CPI203 Improves Lenalidomide and Dexamethasone Activity in in Vitro and in Vivo Models of Multiple Myeloma By Blockade of Ikaros and MYC Signaling. Haematologica. 2017;102(10):1776-1784. PubMed PMID: 28751557.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling. AU - Díaz,Tania, AU - Rodríguez,Vanina, AU - Lozano,Ester, AU - Mena,Mari-Pau, AU - Calderón,Marcos, AU - Rosiñol,Laura, AU - Martínez,Antonio, AU - Tovar,Natalia, AU - Pérez-Galán,Patricia, AU - Bladé,Joan, AU - Roué,Gaël, AU - de Larrea,Carlos Fernández, Y1 - 2017/07/27/ PY - 2017/01/20/received PY - 2017/07/19/accepted PY - 2017/7/29/pubmed PY - 2018/5/22/medline PY - 2017/7/29/entrez SP - 1776 EP - 1784 JF - Haematologica JO - Haematologica VL - 102 IS - 10 N2 - 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. SN - 1592-8721 UR - https://www.unboundmedicine.com/medline/citation/28751557/The_BET_bromodomain_inhibitor_CPI203_improves_lenalidomide_and_dexamethasone_activity_in_in_vitro_and_in_vivo_models_of_multiple_myeloma_by_blockade_of_Ikaros_and_MYC_signaling_ L2 - http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=28751557 DB - PRIME DP - Unbound Medicine ER -