Carregant...
Fitxers
Tipus de document
ArticleVersió
Versió publicadaData de publicació
Tots els drets reservats
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/165869
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.
Títol de la revista
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
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.
Matèries
Matèries (anglès)
Citació
Citació
DÍAZ SÁNCHEZ, Tania, RODRÍGUEZ, Vanina, LOZANO GARCIA, 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. 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.. _Haematologica_. 2017. Vol. 102, núm. 10, pàgs. 1776-1784. [consulta: 8 de abril de 2026]. ISSN: 0390-6078. [Disponible a: https://hdl.handle.net/2445/165869]