title: In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone.
abstract: 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.
authors.affiliation: 1] Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain [2] Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: E M
authors.initials: EM
authors.lastname: Ocio
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Fernández-Lázaro
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: L
authors.initials: L
authors.lastname: San-Segundo
authors.affiliation: Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain.
authors.forename: L
authors.initials: L
authors.lastname: López-Corral
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: L A
authors.initials: LA
authors.lastname: Corchete
authors.affiliation: 1] Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain [2] Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: N C
authors.initials: NC
authors.lastname: Gutiérrez
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Garayoa
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Paíno
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García-Gómez
authors.affiliation: 1] Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain [2] Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Delgado
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: J C
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Díaz-Rodríguez
authors.affiliation: 1] Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain [2] Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: M V
authors.initials: MV
authors.lastname: Mateos
authors.affiliation: Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Couto
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Bjorklund
authors.affiliation: Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas (CIMA), Pamplona, Spain.
authors.forename: J F
authors.initials: JF
authors.lastname: San-Miguel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D000077269:Lenalidomide; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010954:Plasmacytoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: C517975:AZD 6244; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C549921:Crbn protein, mouse; C491396:Ikzf3 protein, mouse; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide; D048049:Extracellular Signal-Regulated MAP Kinases; D000077269:Lenalidomide
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