Sanz Álvarez, MartaMartín-Aparicio, EsterLuque, MelaniZazo, SandraMartínez-Useros, JavierEroles, PilarRovira, AnaAlbanell Mestres, JoanMadoz-Gúrpide, JuanRojo, Federico2022-01-102022-01-102021Sanz-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/cancers131127782072-6694http://hdl.handle.net/10230/52175The 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.application/pdfeng© 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/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/cancers13112778PI3KTAK-228Anti-receptor therapyBreast cancermTORResistanceTrastuzumabinfo:eu-repo/semantics/openAccess