Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response

Sandra Jernström,1,2 Vesa Hongisto,3 Suvi-Katri Leivonen,1,2 Eldri Undlien Due,1 Dagim Shiferaw Tadele,1 Henrik Edgren,4,5 Olli Kallioniemi,4 Merja Perälä,6 Gunhild Mari Mælandsmo,2,7,8 Kristine Kleivi Sahlberg,1,9 1Department of Cancer Genetics, Institute for Ca...

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Autores principales:	Jernström S, Hongisto V, Leivonen SK, Due EU, Tadele DS, Edgren H, Kallioniemi O, Perälä M, Mælandsmo GM, Sahlberg KK
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	ERBB2 drug screening gene expression pharmacogenomics predictors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/5242fb84bf7e40c0a4884802397f2a64
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spelling	oai:doaj.org-article:5242fb84bf7e40c0a4884802397f2a642021-12-02T00:06:02ZDrug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response1179-1314https://doaj.org/article/5242fb84bf7e40c0a4884802397f2a642017-03-01T00:00:00Zhttps://www.dovepress.com/drug-screening-and-genomic-analyses-of-her2-positive-breast-cancer-cel-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Sandra Jernström,1,2 Vesa Hongisto,3 Suvi-Katri Leivonen,1,2 Eldri Undlien Due,1 Dagim Shiferaw Tadele,1 Henrik Edgren,4,5 Olli Kallioniemi,4 Merja Perälä,6 Gunhild Mari Mælandsmo,2,7,8 Kristine Kleivi Sahlberg,1,9 1Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 2KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; 3Misvik Biology Oy, Turku, 4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 5Medisapiens, Helsinki, Finland, 6VTT Technical Research Centre of Finland, Turku, Finland; 7Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 8Institute of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, 9Department of Research, Vestre Viken Hospital Trust, Drammen, Norway Background: Approximately 15%–20% of all diagnosed breast cancers are characterized by amplified and overexpressed HER2 (= ErbB2). These breast cancers are aggressive and have a poor prognosis. Although improvements in treatment have been achieved after the introduction of trastuzumab and lapatinib, many patients do not benefit from these drugs. Therefore, in-depth understanding of the mechanisms behind the treatment responses is essential to find alternative therapeutic strategies.  Materials and methods: Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2-signaling pathway, and molecular mechanisms related to treatment sensitivity were sought. Cell viability was measured, and treatment responses between the cell lines were compared. To search for response predictors and genomic and transcriptomic profiling, PIK3CA mutations and PTEN status were explored and molecular features associated with drug sensitivity sought.  Results: The cell lines were divided into three groups according to the growth-retarding effect induced by trastuzumab and lapatinib. Interestingly, two cell lines insensitive to trastuzumab (KPL4 and SUM190PT) showed sensitivity to an Akt1/2 kinase inhibitor. These cell lines had mutation in PIK3CA and loss of PTEN, suggesting an activated and druggable Akt-signaling pathway. Expression levels of five genes (CDC42, MAPK8, PLCG1, PTK6, and PAK6) were suggested as predictors for the Akt1/2 kinase-inhibitor response.  Conclusion: Targeting the Akt-signaling pathway shows promise in cell lines that do not respond to trastuzumab. In addition, our results indicate that several molecular features determine the growth-retarding effects induced by the drugs, suggesting that parameters other than HER2 amplification/expression should be included as markers for therapy decisions. Keywords: ErbB2, drug screening, gene expression, pharmacogenomics, predictorsJernström SHongisto VLeivonen SKDue EUTadele DSEdgren HKallioniemi OPerälä MMælandsmo GMSahlberg KKDove Medical PressarticleERBB2drug screeninggene expressionpharmacogenomicspredictorsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 9, Pp 185-198 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	ERBB2 drug screening gene expression pharmacogenomics predictors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	ERBB2 drug screening gene expression pharmacogenomics predictors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jernström S Hongisto V Leivonen SK Due EU Tadele DS Edgren H Kallioniemi O Perälä M Mælandsmo GM Sahlberg KK Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
description	Sandra Jernström,1,2 Vesa Hongisto,3 Suvi-Katri Leivonen,1,2 Eldri Undlien Due,1 Dagim Shiferaw Tadele,1 Henrik Edgren,4,5 Olli Kallioniemi,4 Merja Perälä,6 Gunhild Mari Mælandsmo,2,7,8 Kristine Kleivi Sahlberg,1,9 1Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 2KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; 3Misvik Biology Oy, Turku, 4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 5Medisapiens, Helsinki, Finland, 6VTT Technical Research Centre of Finland, Turku, Finland; 7Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 8Institute of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, 9Department of Research, Vestre Viken Hospital Trust, Drammen, Norway Background: Approximately 15%–20% of all diagnosed breast cancers are characterized by amplified and overexpressed HER2 (= ErbB2). These breast cancers are aggressive and have a poor prognosis. Although improvements in treatment have been achieved after the introduction of trastuzumab and lapatinib, many patients do not benefit from these drugs. Therefore, in-depth understanding of the mechanisms behind the treatment responses is essential to find alternative therapeutic strategies.  Materials and methods: Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2-signaling pathway, and molecular mechanisms related to treatment sensitivity were sought. Cell viability was measured, and treatment responses between the cell lines were compared. To search for response predictors and genomic and transcriptomic profiling, PIK3CA mutations and PTEN status were explored and molecular features associated with drug sensitivity sought.  Results: The cell lines were divided into three groups according to the growth-retarding effect induced by trastuzumab and lapatinib. Interestingly, two cell lines insensitive to trastuzumab (KPL4 and SUM190PT) showed sensitivity to an Akt1/2 kinase inhibitor. These cell lines had mutation in PIK3CA and loss of PTEN, suggesting an activated and druggable Akt-signaling pathway. Expression levels of five genes (CDC42, MAPK8, PLCG1, PTK6, and PAK6) were suggested as predictors for the Akt1/2 kinase-inhibitor response.  Conclusion: Targeting the Akt-signaling pathway shows promise in cell lines that do not respond to trastuzumab. In addition, our results indicate that several molecular features determine the growth-retarding effects induced by the drugs, suggesting that parameters other than HER2 amplification/expression should be included as markers for therapy decisions. Keywords: ErbB2, drug screening, gene expression, pharmacogenomics, predictors
format	article
author	Jernström S Hongisto V Leivonen SK Due EU Tadele DS Edgren H Kallioniemi O Perälä M Mælandsmo GM Sahlberg KK
author_facet	Jernström S Hongisto V Leivonen SK Due EU Tadele DS Edgren H Kallioniemi O Perälä M Mælandsmo GM Sahlberg KK
author_sort	Jernström S
title	Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
title_short	Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
title_full	Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
title_fullStr	Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
title_full_unstemmed	Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
title_sort	drug-screening and genomic analyses of her2-positive breast cancer cell lines reveal predictors for treatment response
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/5242fb84bf7e40c0a4884802397f2a64
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Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response

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