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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Autores: Alcon, Clara, Martín, Fernando|||0000-0002-3496-9093, Prada, Estela|||0000-0003-4611-1120, Català-Mora, Jaume|||0000-0003-2152-8579, Soriano, Aroa|||0000-0001-9659-1471, Guillén, Gabriela|||0000-0001-5632-2672, Gallego, Soledad|||0000-0002-4712-9624, Roma, Josep|||0000-0001-7692-6123, Samitier, Josep|||0000-0002-1140-3679, Villanueva, Alejandro|||0000-0001-5164-0006, Montero, Joan|||0000-0002-9192-4836
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:292285
Acceso en línea:https://ddd.uab.cat/record/292285
https://dx.doi.org/urn:doi:10.1038/s41420-022-00959-w
Access Level:acceso abierto
Palabra clave:Targeted therapies
Paediatric cancer
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spelling MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatmentAlcon, ClaraMartín, Fernando|||0000-0002-3496-9093Prada, Estela|||0000-0003-4611-1120Català-Mora, Jaume|||0000-0003-2152-8579Soriano, Aroa|||0000-0001-9659-1471Guillén, Gabriela|||0000-0001-5632-2672Gallego, Soledad|||0000-0002-4712-9624Roma, Josep|||0000-0001-7692-6123Samitier, Josep|||0000-0002-1140-3679Villanueva, Alejandro|||0000-0001-5164-0006Montero, Joan|||0000-0002-9192-4836Targeted therapiesPaediatric cancerTargeted 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.Universitat Autònoma de Barcelona 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/292285https://dx.doi.org/urn:doi:10.1038/s41420-022-00959-wreponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 RYC-2015-18357Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-094533-A-I00Generalitat de Catalunya https://doi.org/10.13039/501100002809 2017SGR1079Generalitat de Catalunya https://doi.org/10.13039/501100002809 2014SGR264Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI19/01320open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2922852026-06-06T12:50:31Z
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
Alcon, Clara
Targeted therapies
Paediatric cancer
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 Alcon, Clara
Martín, Fernando|||0000-0002-3496-9093
Prada, Estela|||0000-0003-4611-1120
Català-Mora, Jaume|||0000-0003-2152-8579
Soriano, Aroa|||0000-0001-9659-1471
Guillén, Gabriela|||0000-0001-5632-2672
Gallego, Soledad|||0000-0002-4712-9624
Roma, Josep|||0000-0001-7692-6123
Samitier, Josep|||0000-0002-1140-3679
Villanueva, Alejandro|||0000-0001-5164-0006
Montero, Joan|||0000-0002-9192-4836
author Alcon, Clara
author_facet Alcon, Clara
Martín, Fernando|||0000-0002-3496-9093
Prada, Estela|||0000-0003-4611-1120
Català-Mora, Jaume|||0000-0003-2152-8579
Soriano, Aroa|||0000-0001-9659-1471
Guillén, Gabriela|||0000-0001-5632-2672
Gallego, Soledad|||0000-0002-4712-9624
Roma, Josep|||0000-0001-7692-6123
Samitier, Josep|||0000-0002-1140-3679
Villanueva, Alejandro|||0000-0001-5164-0006
Montero, Joan|||0000-0002-9192-4836
author_role author
author2 Martín, Fernando|||0000-0002-3496-9093
Prada, Estela|||0000-0003-4611-1120
Català-Mora, Jaume|||0000-0003-2152-8579
Soriano, Aroa|||0000-0001-9659-1471
Guillén, Gabriela|||0000-0001-5632-2672
Gallego, Soledad|||0000-0002-4712-9624
Roma, Josep|||0000-0001-7692-6123
Samitier, Josep|||0000-0002-1140-3679
Villanueva, Alejandro|||0000-0001-5164-0006
Montero, Joan|||0000-0002-9192-4836
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Targeted therapies
Paediatric cancer
topic Targeted therapies
Paediatric cancer
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 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/292285
https://dx.doi.org/urn:doi:10.1038/s41420-022-00959-w
url https://ddd.uab.cat/record/292285
https://dx.doi.org/urn:doi:10.1038/s41420-022-00959-w
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 RYC-2015-18357
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-094533-A-I00
Generalitat de Catalunya https://doi.org/10.13039/501100002809 2017SGR1079
Generalitat de Catalunya https://doi.org/10.13039/501100002809 2014SGR264
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI19/01320
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://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
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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