Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells

Autores
Spender, Lindsay C.; Ferguson, John; Liu, Sijia; Cui, Chao; Girotti, Maria Romina; Sibbet, Gary; Higgs, Ellen; Shuttleworth, Morven K.; Hamilton, Tom; Lorigan, Paul; Weller, Michael; Vincent, David F.; Sansom, Owen J.; Frame, Margaret; Dijke, Peter ten; Marais, Richard; Inman, Gareth J.
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance.
Fil: Spender, Lindsay C.. University of Dundee; Reino Unido. The Beatson Institute for Cancer Research; Reino Unido
Fil: Ferguson, John. The Beatson Institute for Cancer Research; Reino Unido. MedImmune Limited; Reino Unido
Fil: Liu, Sijia. Leiden University; Países Bajos
Fil: Cui, Chao. Leiden University; Países Bajos
Fil: Girotti, Maria Romina. University of Manchester; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Sibbet, Gary. The Beatson Institute for Cancer Research; Reino Unido
Fil: Higgs, Ellen. University of Dundee; Reino Unido
Fil: Shuttleworth, Morven K.. University of Dundee; Reino Unido
Fil: Hamilton, Tom. The Beatson Institute for Cancer Research; Reino Unido
Fil: Lorigan, Paul. University of Manchester; Reino Unido
Fil: Weller, Michael. Universitat Zurich; Suiza
Fil: Vincent, David F.. The Beatson Institute for Cancer Research; Reino Unido
Fil: Sansom, Owen J.. The Beatson Institute for Cancer Research; Reino Unido
Fil: Frame, Margaret. University of Edinburgh; Reino Unido
Fil: Dijke, Peter ten. Leiden University; Países Bajos
Fil: Marais, Richard. University of Manchester; Reino Unido
Fil: Inman, Gareth J.. The Beatson Institute for Cancer Research; Reino Unido. University of Dundee; Reino Unido
Materia
MELANOMA
RESISTANCE
TGFB
BRAF
VEMURAFENIB
PLX 4720
TGF BETA
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/24320
Acceder
id CONICETDig_3f103257bd0f47235e900a7f05bb6e66
oai_identifier_str oai:ri.conicet.gov.ar:11336/24320
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cellsSpender, Lindsay C.Ferguson, JohnLiu, SijiaCui, ChaoGirotti, Maria RominaSibbet, GaryHiggs, EllenShuttleworth, Morven K.Hamilton, TomLorigan, PaulWeller, MichaelVincent, David F.Sansom, Owen J.Frame, MargaretDijke, Peter tenMarais, RichardInman, Gareth J.MELANOMARESISTANCETGFBBRAFVEMURAFENIBPLX 4720TGF BETAhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance.Fil: Spender, Lindsay C.. University of Dundee; Reino Unido. The Beatson Institute for Cancer Research; Reino UnidoFil: Ferguson, John. The Beatson Institute for Cancer Research; Reino Unido. MedImmune Limited; Reino UnidoFil: Liu, Sijia. Leiden University; Países BajosFil: Cui, Chao. Leiden University; Países BajosFil: Girotti, Maria Romina. University of Manchester; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sibbet, Gary. The Beatson Institute for Cancer Research; Reino UnidoFil: Higgs, Ellen. University of Dundee; Reino UnidoFil: Shuttleworth, Morven K.. University of Dundee; Reino UnidoFil: Hamilton, Tom. The Beatson Institute for Cancer Research; Reino UnidoFil: Lorigan, Paul. University of Manchester; Reino UnidoFil: Weller, Michael. Universitat Zurich; SuizaFil: Vincent, David F.. The Beatson Institute for Cancer Research; Reino UnidoFil: Sansom, Owen J.. The Beatson Institute for Cancer Research; Reino UnidoFil: Frame, Margaret. University of Edinburgh; Reino UnidoFil: Dijke, Peter ten. Leiden University; Países BajosFil: Marais, Richard. University of Manchester; Reino UnidoFil: Inman, Gareth J.. The Beatson Institute for Cancer Research; Reino Unido. University of Dundee; Reino UnidoImpact journals2016-11-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/24320Spender, Lindsay C.; Ferguson, John; Liu, Sijia; Cui, Chao; Girotti, Maria Romina; et al.; Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells; Impact journals; Oncotarget; 7; 50; 9-11-2016; 81995-820121949-25531949-2553CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=13226info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.13226info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347669/info:eu-repo/semantics/altIdentifier/pmid/27835901info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:54:32Zoai:ri.conicet.gov.ar:11336/24320instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:54:33.195CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
title Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
spellingShingle Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
Spender, Lindsay C.
MELANOMA
RESISTANCE
TGFB
BRAF
VEMURAFENIB
PLX 4720
TGF BETA
title_short Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
title_full Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
title_fullStr Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
title_full_unstemmed Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
title_sort Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
dc.creator.none.fl_str_mv Spender, Lindsay C.
Ferguson, John
Liu, Sijia
Cui, Chao
Girotti, Maria Romina
Sibbet, Gary
Higgs, Ellen
Shuttleworth, Morven K.
Hamilton, Tom
Lorigan, Paul
Weller, Michael
Vincent, David F.
Sansom, Owen J.
Frame, Margaret
Dijke, Peter ten
Marais, Richard
Inman, Gareth J.
author Spender, Lindsay C.
author_facet Spender, Lindsay C.
Ferguson, John
Liu, Sijia
Cui, Chao
Girotti, Maria Romina
Sibbet, Gary
Higgs, Ellen
Shuttleworth, Morven K.
Hamilton, Tom
Lorigan, Paul
Weller, Michael
Vincent, David F.
Sansom, Owen J.
Frame, Margaret
Dijke, Peter ten
Marais, Richard
Inman, Gareth J.
author_role author
author2 Ferguson, John
Liu, Sijia
Cui, Chao
Girotti, Maria Romina
Sibbet, Gary
Higgs, Ellen
Shuttleworth, Morven K.
Hamilton, Tom
Lorigan, Paul
Weller, Michael
Vincent, David F.
Sansom, Owen J.
Frame, Margaret
Dijke, Peter ten
Marais, Richard
Inman, Gareth J.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MELANOMA
RESISTANCE
TGFB
BRAF
VEMURAFENIB
PLX 4720
TGF BETA
topic MELANOMA
RESISTANCE
TGFB
BRAF
VEMURAFENIB
PLX 4720
TGF BETA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance.
Fil: Spender, Lindsay C.. University of Dundee; Reino Unido. The Beatson Institute for Cancer Research; Reino Unido
Fil: Ferguson, John. The Beatson Institute for Cancer Research; Reino Unido. MedImmune Limited; Reino Unido
Fil: Liu, Sijia. Leiden University; Países Bajos
Fil: Cui, Chao. Leiden University; Países Bajos
Fil: Girotti, Maria Romina. University of Manchester; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Sibbet, Gary. The Beatson Institute for Cancer Research; Reino Unido
Fil: Higgs, Ellen. University of Dundee; Reino Unido
Fil: Shuttleworth, Morven K.. University of Dundee; Reino Unido
Fil: Hamilton, Tom. The Beatson Institute for Cancer Research; Reino Unido
Fil: Lorigan, Paul. University of Manchester; Reino Unido
Fil: Weller, Michael. Universitat Zurich; Suiza
Fil: Vincent, David F.. The Beatson Institute for Cancer Research; Reino Unido
Fil: Sansom, Owen J.. The Beatson Institute for Cancer Research; Reino Unido
Fil: Frame, Margaret. University of Edinburgh; Reino Unido
Fil: Dijke, Peter ten. Leiden University; Países Bajos
Fil: Marais, Richard. University of Manchester; Reino Unido
Fil: Inman, Gareth J.. The Beatson Institute for Cancer Research; Reino Unido. University of Dundee; Reino Unido
description Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance.
publishDate 2016
dc.date.none.fl_str_mv 2016-11-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/24320
Spender, Lindsay C.; Ferguson, John; Liu, Sijia; Cui, Chao; Girotti, Maria Romina; et al.; Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells; Impact journals; Oncotarget; 7; 50; 9-11-2016; 81995-82012
1949-2553
1949-2553
CONICET Digital
CONICET
url http://hdl.handle.net/11336/24320
identifier_str_mv Spender, Lindsay C.; Ferguson, John; Liu, Sijia; Cui, Chao; Girotti, Maria Romina; et al.; Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells; Impact journals; Oncotarget; 7; 50; 9-11-2016; 81995-82012
1949-2553
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=13226
info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.13226
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347669/
info:eu-repo/semantics/altIdentifier/pmid/27835901
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact journals
publisher.none.fl_str_mv Impact journals
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269291896897536
score 13.13397

Publicaciones similares