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

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http://hdl.handle.net/10138/241059

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Jernström , S , Hongisto , V , Leivonen , S-K , Due , E U , Tadele , D S , Edgren , H , Kallioniemi , O , Perälä , M , Mlandsmo , G M & Sahlberg , K K 2017 , ' Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response ' , Breast Cancer: Targets and Therapy , vol. 9 , pp. 185-198 . https://doi.org/10.2147/BCTT.S115600

Title: Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
Author: Jernström, Sandra; Hongisto, Vesa; Leivonen, Suvi-Katri; Due, Eldri Undlien; Tadele, Dagim Shiferaw; Edgren, Henrik; Kallioniemi, Olli; Perälä, Merja; Mlandsmo, Gunhild Mari; Sahlberg, Kristine Kleivi
Contributor: University of Helsinki, University of Oslo
University of Helsinki, Olli-Pekka Kallioniemi / Principal Investigator
Date: 2017
Language: eng
Number of pages: 14
Belongs to series: Breast Cancer: Targets and Therapy
ISSN: 1179-1314
URI: http://hdl.handle.net/10138/241059
Abstract: 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.
Subject: ErbB2
drug screening
gene expression
pharmacogenomics
predictors
TRASTUZUMAB RESISTANCE
ANTITUMOR-ACTIVITY
ERBB RECEPTORS
PI3K PATHWAY
COPY NUMBER
OPEN-LABEL
LAPATINIB
EXPRESSION
MUTATIONS
PTEN
3122 Cancers
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