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

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• dc.contributor.author Sanz Álvarez, Marta
• dc.contributor.author Martín-Aparicio, Ester
• dc.contributor.author Luque, Melani
• dc.contributor.author Zazo, Sandra
• dc.contributor.author Martínez-Useros, Javier
• dc.contributor.author Eroles, Pilar
• dc.contributor.author Rovira, Ana
• dc.contributor.author Albanell Mestres, Joan
• dc.contributor.author Madoz-Gúrpide, Juan
• dc.contributor.author Rojo, Federico
• dc.date.accessioned 2022-01-10T11:49:19Z
• dc.date.available 2022-01-10T11:49:19Z
• dc.date.issued 2021
• dc.description.abstract 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Sanz-Álvarez M, Martín-Aparicio E, Luque M, Zazo S, Martínez-Useros J, Eroles P, Rovira A, Albanell J, Madoz-Gúrpide J, Rojo F. The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models. Cancers (Basel). 2021;13(11):2778. DOI: 10.3390/cancers13112778
• dc.identifier.doi http://dx.doi.org/10.3390/cancers13112778
• dc.identifier.issn 2072-6694
• dc.identifier.uri http://hdl.handle.net/10230/52175
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Cancers (Basel). 2021;13(11):2778
• dc.rights © 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/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword PI3K
• dc.subject.keyword TAK-228
• dc.subject.keyword Anti-receptor therapy
• dc.subject.keyword Breast cancer
• dc.subject.keyword mTOR
• dc.subject.keyword Resistance
• dc.subject.keyword Trastuzumab
• dc.title The novel oral mTORC1/2 inhibitor TAK-228 reverses trastuzumab resistance in HER2-positive breast cancer models
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion