Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

Background: RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activ...

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Autores: Zaballos, Miguel A., Acuña-Ruiz, Adrián, Morante, Marta, Riesco-Eizaguirre, Garcilaso, Crespo, Piero, Santisteban, Pilar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/285032
Acceso en línea:http://hdl.handle.net/10261/285032
Access Level:acceso abierto
Palabra clave:Thyroid cancer
DEL-22379
ERK dimerization
BRAF
RAS
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oai_identifier_str oai:digital.csic.es:10261/285032
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
title Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
spellingShingle Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
Zaballos, Miguel A.
Thyroid cancer
DEL-22379
ERK dimerization
BRAF
RAS
title_short Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
title_full Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
title_fullStr Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
title_full_unstemmed Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
title_sort Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer
dc.creator.none.fl_str_mv Zaballos, Miguel A.
Acuña-Ruiz, Adrián
Morante, Marta
Riesco-Eizaguirre, Garcilaso
Crespo, Piero
Santisteban, Pilar
author Zaballos, Miguel A.
author_facet Zaballos, Miguel A.
Acuña-Ruiz, Adrián
Morante, Marta
Riesco-Eizaguirre, Garcilaso
Crespo, Piero
Santisteban, Pilar
author_role author
author2 Acuña-Ruiz, Adrián
Morante, Marta
Riesco-Eizaguirre, Garcilaso
Crespo, Piero
Santisteban, Pilar
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Asociación Española Contra el Cáncer
Comunidad de Madrid
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Thyroid cancer
DEL-22379
ERK dimerization
BRAF
RAS
topic Thyroid cancer
DEL-22379
ERK dimerization
BRAF
RAS
description Background: RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo. Methods: We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC. Results: DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions. Conclusions: Our findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
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Publisher's version
info:eu-repo/semantics/publishedVersion
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status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/285032
url http://hdl.handle.net/10261/285032
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/MINECO//SAF2016-75531-R
B2017/BMD-3724/Tironet2
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105303RB-I00
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http://dx.doi.org/10.1007/s00018-022-04530-9
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dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancerZaballos, Miguel A.Acuña-Ruiz, AdriánMorante, MartaRiesco-Eizaguirre, GarcilasoCrespo, PieroSantisteban, PilarThyroid cancerDEL-22379ERK dimerizationBRAFRASBackground: RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo. Methods: We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC. Results: DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions. Conclusions: Our findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.This work was supported by a grant from the Asociación Española Contra el Cancer (AECC; GCB141423113), jointly awarded to PS, PC and GR-E, and by the following national grants: SAF2016-75531-R (MINECO/FEDER, UE); B2017/BMD-3724 Tironet2 (Comunidad de Madrid) and PID2019-105303RB-I00/AEI/10.13.039/501100011033 from MICIN (to PS); RTI2018-096658B-100/AEI from MICIU/FEDER, UE) (to PC); PI14/01980 from Instituto Salud Carlos III (ISCIII) (to GR-E). PS, PC, GR-E and MAZ are members of CIBERONC ISCIII. MAZ, is a postdoctoral researcher funded by grant AECC-GCB141423113; AA-R was funded by an FPI fellowship from MINECO (SAF2013-44709-R) and a postdoctoral fellowship AECC-GCB141423113.Springer NatureAsociación Española Contra el CáncerComunidad de MadridAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Instituto de Salud Carlos IIIMinisterio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/285032reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2016-75531-RB2017/BMD-3724/Tironet2info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105303RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096658-B-I00info:eu-repo/grantAgreement/MINECO//SAF2013-44709-Rhttp://dx.doi.org/10.1007/s00018-022-04530-9Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2850322026-05-22T06:33:51Z
score 15,811543

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