Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells

Abstract Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 t...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yumi Fujimoto, Tomoko Yamamori Morita, Akihiro Ohashi, Hiroshi Haeno, Yumi Hakozaki, Masanori Fujii, Yukie Kashima, Susumu S. Kobayashi, Toru Mukohara
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/910a347264864bb197702e0d7f5cb41e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:910a347264864bb197702e0d7f5cb41e
record_format	dspace
spelling	oai:doaj.org-article:910a347264864bb197702e0d7f5cb41e2021-12-02T15:11:50ZCombination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells10.1038/s41598-020-78646-y2045-2322https://doaj.org/article/910a347264864bb197702e0d7f5cb41e2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78646-yhttps://doaj.org/toc/2045-2322Abstract Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.Yumi FujimotoTomoko Yamamori MoritaAkihiro OhashiHiroshi HaenoYumi HakozakiMasanori FujiiYukie KashimaSusumu S. KobayashiToru MukoharaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yumi Fujimoto Tomoko Yamamori Morita Akihiro Ohashi Hiroshi Haeno Yumi Hakozaki Masanori Fujii Yukie Kashima Susumu S. Kobayashi Toru Mukohara Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells
description	Abstract Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.
format	article
author	Yumi Fujimoto Tomoko Yamamori Morita Akihiro Ohashi Hiroshi Haeno Yumi Hakozaki Masanori Fujii Yukie Kashima Susumu S. Kobayashi Toru Mukohara
author_facet	Yumi Fujimoto Tomoko Yamamori Morita Akihiro Ohashi Hiroshi Haeno Yumi Hakozaki Masanori Fujii Yukie Kashima Susumu S. Kobayashi Toru Mukohara
author_sort	Yumi Fujimoto
title	Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells
title_short	Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells
title_full	Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells
title_fullStr	Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells
title_full_unstemmed	Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells
title_sort	combination treatment with a pi3k/akt/mtor pathway inhibitor overcomes resistance to anti-her2 therapy in pik3ca-mutant her2-positive breast cancer cells
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/910a347264864bb197702e0d7f5cb41e
work_keys_str_mv	AT yumifujimoto combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT tomokoyamamorimorita combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT akihiroohashi combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT hiroshihaeno combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT yumihakozaki combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT masanorifujii combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT yukiekashima combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT susumuskobayashi combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells AT torumukohara combinationtreatmentwithapi3kaktmtorpathwayinhibitorovercomesresistancetoantiher2therapyinpik3camutanther2positivebreastcancercells
_version_	1718387644736471040

Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells

Ejemplares similares