In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone

[EN]The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclin...

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Autores: Ocio, E M, Fernández-Lázaro, D, San-Segundo, L, López Corral, Lucía, Corchete, L A, Gutiérrez, N C, Garayoa, M, Paíno Gómez, María Teresa, García-Gómez, A, Delgado, M, Montero González, Juan Carlos, Díaz Rodríguez, María Elena, Mateos Manteca, María Victoria, Pandiella Pandiella , Alonso, Couto, S, Wang, M, Bjorklund, C C, San-Miguel, J F
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2014
País:España
Institución:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/162485
Acceso en línea:http://hdl.handle.net/10366/162485
Access Level:acceso abierto
Palabra clave:Drug Resistance
Murine model
Lenalidomide
Pomalidomide
IMiDs
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spelling In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasoneOcio, E MFernández-Lázaro, DSan-Segundo, LLópez Corral, LucíaCorchete, L AGutiérrez, N CGarayoa, MPaíno Gómez, María TeresaGarcía-Gómez, ADelgado, MMontero González, Juan CarlosDíaz Rodríguez, María ElenaMateos Manteca, María VictoriaPandiella Pandiella , AlonsoCouto, SWang, MBjorklund, C CSan-Miguel, J FDrug ResistanceMurine modelLenalidomidePomalidomideIMiDs[EN]The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.202520252014info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttp://hdl.handle.net/10366/162485reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésPI11/01465GCB120981SANRD06/0020/0006RD12/0036/0058RD12/0036/0003AECCAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1624852026-06-07T06:28:51Z
dc.title.none.fl_str_mv In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
title In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
spellingShingle In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
Ocio, E M
Drug Resistance
Murine model
Lenalidomide
Pomalidomide
IMiDs
title_short In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
title_full In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
title_fullStr In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
title_full_unstemmed In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
title_sort In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
dc.creator.none.fl_str_mv Ocio, E M
Fernández-Lázaro, D
San-Segundo, L
López Corral, Lucía
Corchete, L A
Gutiérrez, N C
Garayoa, M
Paíno Gómez, María Teresa
García-Gómez, A
Delgado, M
Montero González, Juan Carlos
Díaz Rodríguez, María Elena
Mateos Manteca, María Victoria
Pandiella Pandiella , Alonso
Couto, S
Wang, M
Bjorklund, C C
San-Miguel, J F
author Ocio, E M
author_facet Ocio, E M
Fernández-Lázaro, D
San-Segundo, L
López Corral, Lucía
Corchete, L A
Gutiérrez, N C
Garayoa, M
Paíno Gómez, María Teresa
García-Gómez, A
Delgado, M
Montero González, Juan Carlos
Díaz Rodríguez, María Elena
Mateos Manteca, María Victoria
Pandiella Pandiella , Alonso
Couto, S
Wang, M
Bjorklund, C C
San-Miguel, J F
author_role author
author2 Fernández-Lázaro, D
San-Segundo, L
López Corral, Lucía
Corchete, L A
Gutiérrez, N C
Garayoa, M
Paíno Gómez, María Teresa
García-Gómez, A
Delgado, M
Montero González, Juan Carlos
Díaz Rodríguez, María Elena
Mateos Manteca, María Victoria
Pandiella Pandiella , Alonso
Couto, S
Wang, M
Bjorklund, C C
San-Miguel, J F
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Drug Resistance
Murine model
Lenalidomide
Pomalidomide
IMiDs
topic Drug Resistance
Murine model
Lenalidomide
Pomalidomide
IMiDs
description [EN]The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.
publishDate 2014
dc.date.none.fl_str_mv 2014
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/162485
url http://hdl.handle.net/10366/162485
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PI11/01465
GCB120981SAN
RD06/0020/0006
RD12/0036/0058
RD12/0036/0003
AECC
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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