The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models

The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in...

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Detalles Bibliográficos
Autores: Sanz Álvarez, Marta, Martín-Aparicio, Ester, Luque, Melani, Zazo, Sandra, Martínez-Useros, Javier, Eroles, Pilar, Rovira, Ana, Albanell Mestres, Joan, Madoz-Gúrpide, Juan, Rojo, Federico
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
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:10230/52175
Acceso en línea:http://hdl.handle.net/10230/52175
http://dx.doi.org/10.3390/cancers13112778
Access Level:acceso abierto
Palabra clave:PI3K
TAK-228
Anti-receptor therapy
Breast cancer
mTOR
Resistance
Trastuzumab
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spelling The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer modelsSanz Álvarez, MartaMartín-Aparicio, EsterLuque, MelaniZazo, SandraMartínez-Useros, JavierEroles, PilarRovira, AnaAlbanell Mestres, JoanMadoz-Gúrpide, JuanRojo, FedericoPI3KTAK-228Anti-receptor therapyBreast cancermTORResistanceTrastuzumabThe use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.MDPI202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/52175http://dx.doi.org/10.3390/cancers13112778reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCancers (Basel). 2021;13(11):2778© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/521752026-05-29T05:05:01Z
dc.title.none.fl_str_mv The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
title The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
spellingShingle The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
Sanz Álvarez, Marta
PI3K
TAK-228
Anti-receptor therapy
Breast cancer
mTOR
Resistance
Trastuzumab
title_short The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
title_full The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
title_fullStr The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
title_full_unstemmed The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
title_sort The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
dc.creator.none.fl_str_mv Sanz Álvarez, Marta
Martín-Aparicio, Ester
Luque, Melani
Zazo, Sandra
Martínez-Useros, Javier
Eroles, Pilar
Rovira, Ana
Albanell Mestres, Joan
Madoz-Gúrpide, Juan
Rojo, Federico
author Sanz Álvarez, Marta
author_facet Sanz Álvarez, Marta
Martín-Aparicio, Ester
Luque, Melani
Zazo, Sandra
Martínez-Useros, Javier
Eroles, Pilar
Rovira, Ana
Albanell Mestres, Joan
Madoz-Gúrpide, Juan
Rojo, Federico
author_role author
author2 Martín-Aparicio, Ester
Luque, Melani
Zazo, Sandra
Martínez-Useros, Javier
Eroles, Pilar
Rovira, Ana
Albanell Mestres, Joan
Madoz-Gúrpide, Juan
Rojo, Federico
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PI3K
TAK-228
Anti-receptor therapy
Breast cancer
mTOR
Resistance
Trastuzumab
topic PI3K
TAK-228
Anti-receptor therapy
Breast cancer
mTOR
Resistance
Trastuzumab
description The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.
publishDate 2021
dc.date.none.fl_str_mv 2021
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 http://hdl.handle.net/10230/52175
http://dx.doi.org/10.3390/cancers13112778
url http://hdl.handle.net/10230/52175
http://dx.doi.org/10.3390/cancers13112778
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cancers (Basel). 2021;13(11):2778
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv 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 15,812429

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