Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.

Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increase...

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Autores: Nagarajah, James, Le, Mina, Knauf, Jeffrey A, Ferrandino, Giuseppe, Montero-Conde, Cristina, Pillarsetty, Nagavarakishore, Bolaender, Alexander, Irwin, Christopher, Krishnamoorthy, Gnana Prakasam, Saqcena, Mahesh, Larson, Steven M, Ho, Alan L, Seshan, Venkatraman, Ishii, Nobuya, Carrasco, Nancy, Rosen, Neal, Weber, Wolfgang A, Fagin, James A
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/27215
Acceso en línea:https://hdl.handle.net/20.500.12105/27215
Access Level:acceso abierto
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spelling Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.Nagarajah, JamesLe, MinaKnauf, Jeffrey AFerrandino, GiuseppeMontero-Conde, CristinaPillarsetty, NagavarakishoreBolaender, AlexanderIrwin, ChristopherKrishnamoorthy, Gnana PrakasamSaqcena, MaheshLarson, Steven MHo, Alan LSeshan, VenkatramanIshii, NobuyaCarrasco, NancyRosen, NealWeber, Wolfgang AFagin, James ARadioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.American Society for Clinical Investigation20262026-02-0920162016-11-0120162016-11-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://hdl.handle.net/20.500.12105/27215reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/272152026-06-12T12:43:37Z
dc.title.none.fl_str_mv Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
title Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
spellingShingle Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
Nagarajah, James
title_short Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
title_full Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
title_fullStr Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
title_full_unstemmed Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
title_sort Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
dc.creator.none.fl_str_mv Nagarajah, James
Le, Mina
Knauf, Jeffrey A
Ferrandino, Giuseppe
Montero-Conde, Cristina
Pillarsetty, Nagavarakishore
Bolaender, Alexander
Irwin, Christopher
Krishnamoorthy, Gnana Prakasam
Saqcena, Mahesh
Larson, Steven M
Ho, Alan L
Seshan, Venkatraman
Ishii, Nobuya
Carrasco, Nancy
Rosen, Neal
Weber, Wolfgang A
Fagin, James A
author Nagarajah, James
author_facet Nagarajah, James
Le, Mina
Knauf, Jeffrey A
Ferrandino, Giuseppe
Montero-Conde, Cristina
Pillarsetty, Nagavarakishore
Bolaender, Alexander
Irwin, Christopher
Krishnamoorthy, Gnana Prakasam
Saqcena, Mahesh
Larson, Steven M
Ho, Alan L
Seshan, Venkatraman
Ishii, Nobuya
Carrasco, Nancy
Rosen, Neal
Weber, Wolfgang A
Fagin, James A
author_role author
author2 Le, Mina
Knauf, Jeffrey A
Ferrandino, Giuseppe
Montero-Conde, Cristina
Pillarsetty, Nagavarakishore
Bolaender, Alexander
Irwin, Christopher
Krishnamoorthy, Gnana Prakasam
Saqcena, Mahesh
Larson, Steven M
Ho, Alan L
Seshan, Venkatraman
Ishii, Nobuya
Carrasco, Nancy
Rosen, Neal
Weber, Wolfgang A
Fagin, James A
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
description Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016-11-01
2016
2016-11-01
2026
2026-02-09
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
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://hdl.handle.net/20.500.12105/27215
url https://hdl.handle.net/20.500.12105/27215
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-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/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-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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