Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Abstract Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sen...

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Autores principales:	Aryan Stanley, G. Hossein Ashrafi, Alan M. Seddon, Helmout Modjtahedi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f0000ac46d14162b7c8ab0dbd956d8f
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spelling	oai:doaj.org-article:2f0000ac46d14162b7c8ab0dbd956d8f2021-12-02T15:18:53ZSynergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines10.1038/s41598-017-04301-82045-2322https://doaj.org/article/2f0000ac46d14162b7c8ab0dbd956d8f2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04301-8https://doaj.org/toc/2045-2322Abstract Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Our results suggest that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation.Aryan StanleyG. Hossein AshrafiAlan M. SeddonHelmout ModjtahediNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aryan Stanley G. Hossein Ashrafi Alan M. Seddon Helmout Modjtahedi Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines
description	Abstract Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Our results suggest that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation.
format	article
author	Aryan Stanley G. Hossein Ashrafi Alan M. Seddon Helmout Modjtahedi
author_facet	Aryan Stanley G. Hossein Ashrafi Alan M. Seddon Helmout Modjtahedi
author_sort	Aryan Stanley
title	Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines
title_short	Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines
title_full	Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines
title_fullStr	Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines
title_full_unstemmed	Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines
title_sort	synergistic effects of various her inhibitors in combination with igf-1r, c-met and src targeting agents in breast cancer cell lines
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2f0000ac46d14162b7c8ab0dbd956d8f
work_keys_str_mv	AT aryanstanley synergisticeffectsofvariousherinhibitorsincombinationwithigf1rcmetandsrctargetingagentsinbreastcancercelllines AT ghosseinashrafi synergisticeffectsofvariousherinhibitorsincombinationwithigf1rcmetandsrctargetingagentsinbreastcancercelllines AT alanmseddon synergisticeffectsofvariousherinhibitorsincombinationwithigf1rcmetandsrctargetingagentsinbreastcancercelllines AT helmoutmodjtahedi synergisticeffectsofvariousherinhibitorsincombinationwithigf1rcmetandsrctargetingagentsinbreastcancercelllines
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Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

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