Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those...

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Autores: Paíno, Teresa, González Méndez, Lorena, San Segundo, Laura, Corchete, Luis A., Hernández García, Susana, Díaz Tejedor, Andrea, Algarín, Esperanza M., Mogollón, Pedro, Martín Sánchez, Montserrat, Gutiérrez, Norma C., Mateos, María Victoria, Garayoa, Mercedes, Ocio San Miguel, Enrique María|||0000-0002-5765-0085
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/21517
Acceso en línea:http://hdl.handle.net/10902/21517
Access Level:acceso abierto
Palabra clave:Drug Combination
Multiple Myeloma
Pan-PIM Kinase Inhibitor
Protein Translation
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spelling Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple MyelomaPaíno, TeresaGonzález Méndez, LorenaSan Segundo, LauraCorchete, Luis A.Hernández García, SusanaDíaz Tejedor, AndreaAlgarín, Esperanza M.Mogollón, PedroMartín Sánchez, MontserratGutiérrez, Norma C.Mateos, María VictoriaGarayoa, MercedesOcio San Miguel, Enrique María|||0000-0002-5765-0085Drug CombinationMultiple MyelomaPan-PIM Kinase InhibitorProtein TranslationBackground: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.This work was supported by funding from Spanish FIS (PI15/00067, PI15/02156 and PI18/01600) and FEDER, AECC (GCB120981SAN), Junta de Castilla y León, Consejería de Sanidad (GRS 862/A/13 and BIO/SA05/14), Fundación Memoria de D. Samuel Solórzano Barruso of the University of Salamanca (FS/22-2015), Fundación Ramón Areces (FRA16/003), Sociedad Española de Hematología y Hemoterapia and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. E.M.O. was supported by an Inplant grant from IDIVAL. T.P. is supported by a grant from AECC (INVES18043PAÍN).MDPIUniversidad de Cantabria20202020-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttp://hdl.handle.net/10902/21517Cancers (Basel) . 2020 Sep 24;12(10):2743reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/215172026-06-02T12:39:31Z
dc.title.none.fl_str_mv Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
title Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
spellingShingle Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
Paíno, Teresa
Drug Combination
Multiple Myeloma
Pan-PIM Kinase Inhibitor
Protein Translation
title_short Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
title_full Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
title_fullStr Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
title_full_unstemmed Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
title_sort Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
dc.creator.none.fl_str_mv Paíno, Teresa
González Méndez, Lorena
San Segundo, Laura
Corchete, Luis A.
Hernández García, Susana
Díaz Tejedor, Andrea
Algarín, Esperanza M.
Mogollón, Pedro
Martín Sánchez, Montserrat
Gutiérrez, Norma C.
Mateos, María Victoria
Garayoa, Mercedes
Ocio San Miguel, Enrique María|||0000-0002-5765-0085
author Paíno, Teresa
author_facet Paíno, Teresa
González Méndez, Lorena
San Segundo, Laura
Corchete, Luis A.
Hernández García, Susana
Díaz Tejedor, Andrea
Algarín, Esperanza M.
Mogollón, Pedro
Martín Sánchez, Montserrat
Gutiérrez, Norma C.
Mateos, María Victoria
Garayoa, Mercedes
Ocio San Miguel, Enrique María|||0000-0002-5765-0085
author_role author
author2 González Méndez, Lorena
San Segundo, Laura
Corchete, Luis A.
Hernández García, Susana
Díaz Tejedor, Andrea
Algarín, Esperanza M.
Mogollón, Pedro
Martín Sánchez, Montserrat
Gutiérrez, Norma C.
Mateos, María Victoria
Garayoa, Mercedes
Ocio San Miguel, Enrique María|||0000-0002-5765-0085
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv Drug Combination
Multiple Myeloma
Pan-PIM Kinase Inhibitor
Protein Translation
topic Drug Combination
Multiple Myeloma
Pan-PIM Kinase Inhibitor
Protein Translation
description Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10902/21517
url http://hdl.handle.net/10902/21517
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Cancers (Basel) . 2020 Sep 24;12(10):2743
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300724

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