MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment

Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targ...

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Detalles Bibliográficos
Autores: Alcón, Clara, Martín, Fernando, Prada, Estela, Mora Graupera, Jaume, Soriano, Aroa, Guillén, Gabriela, Gallego, Soledad, Roma, Josep, Samitier i Martí, Josep, Villanueva, Alberto, Montero, Joan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/185172
Acceso en línea:https://hdl.handle.net/2445/185172
Access Level:acceso abierto
Palabra clave:Terapèutica
Càncer
Proteïnes supressores de tumors
Therapeutics
Cancer
Tumor suppressor protein
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spelling MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatmentAlcón, ClaraMartín, FernandoPrada, EstelaMora Graupera, JaumeSoriano, AroaGuillén, GabrielaGallego, SoledadRoma, JosepSamitier i Martí, JosepVillanueva, AlbertoMontero, JoanTerapèuticaCàncerProteïnes supressores de tumorsTherapeuticsCancerTumor suppressor proteinTargeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse. We observed that the MEK1/2 inhibitor trametinib rapidly depleted the pro-apoptotic protein NOXA, thus increasing MCL-1 availability. Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.2022202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion12 p.application/pdfhttps://hdl.handle.net/2445/185172Articles publicats en revistes (Enginyeria Electrònica i Biomèdica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Ingléshttps://doi.org/10.1038/s41420-022-00959-wCell Death Discov, 2022, vol. 8, num.172https://doi.org/10.1038/s41420-022-00959-wcc by (c) Alcon, Clara et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1851722026-05-29T05:05:01Z
dc.title.none.fl_str_mv MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
title MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
spellingShingle MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
Alcón, Clara
Terapèutica
Càncer
Proteïnes supressores de tumors
Therapeutics
Cancer
Tumor suppressor protein
title_short MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
title_full MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
title_fullStr MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
title_full_unstemmed MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
title_sort MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
dc.creator.none.fl_str_mv Alcón, Clara
Martín, Fernando
Prada, Estela
Mora Graupera, Jaume
Soriano, Aroa
Guillén, Gabriela
Gallego, Soledad
Roma, Josep
Samitier i Martí, Josep
Villanueva, Alberto
Montero, Joan
author Alcón, Clara
author_facet Alcón, Clara
Martín, Fernando
Prada, Estela
Mora Graupera, Jaume
Soriano, Aroa
Guillén, Gabriela
Gallego, Soledad
Roma, Josep
Samitier i Martí, Josep
Villanueva, Alberto
Montero, Joan
author_role author
author2 Martín, Fernando
Prada, Estela
Mora Graupera, Jaume
Soriano, Aroa
Guillén, Gabriela
Gallego, Soledad
Roma, Josep
Samitier i Martí, Josep
Villanueva, Alberto
Montero, Joan
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Terapèutica
Càncer
Proteïnes supressores de tumors
Therapeutics
Cancer
Tumor suppressor protein
topic Terapèutica
Càncer
Proteïnes supressores de tumors
Therapeutics
Cancer
Tumor suppressor protein
description Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse. We observed that the MEK1/2 inhibitor trametinib rapidly depleted the pro-apoptotic protein NOXA, thus increasing MCL-1 availability. Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/185172
url https://hdl.handle.net/2445/185172
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1038/s41420-022-00959-w
Cell Death Discov, 2022, vol. 8, num.172
https://doi.org/10.1038/s41420-022-00959-w
dc.rights.none.fl_str_mv cc by (c) Alcon, Clara et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Alcon, Clara et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 12 p.
application/pdf
dc.source.none.fl_str_mv Articles publicats en revistes (Enginyeria Electrònica i Biomèdica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.228081

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