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

Sandra Jernström, Vesa Hongisto, Suvi Leivonen, Eldri Due, Dagim Tadele, Henrik Edgren, Olli Kallioniemi, Merja Perälä, Gunhild Mælandsmo, Kristine Sahlberg

    Research output: Contribution to journalArticleScientificpeer-review

    8 Citations (Scopus)

    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.
    Original languageEnglish
    Article numberA22
    Pages (from-to)185-198
    Number of pages14
    JournalBreast Cancer
    Volume9
    DOIs
    Publication statusPublished - 21 Mar 2017
    MoE publication typeA1 Journal article-refereed

    Fingerprint

    Preclinical Drug Evaluations
    Breast Neoplasms
    Cell Line
    Phosphotransferases
    Therapeutics
    Pharmaceutical Preparations
    Mutation
    Protein Transport
    Growth
    Cell Survival
    Trastuzumab
    Genes

    Keywords

    • drug screening
    • ErbB2
    • gene expression
    • pharmacogenomics
    • predictors

    Cite this

    Jernström, S., Hongisto, V., Leivonen, S., Due, E., Tadele, D., Edgren, H., ... Sahlberg, K. (2017). Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response. Breast Cancer, 9, 185-198. [A22]. https://doi.org/10.2147/BCTT.S115600
    Jernström, Sandra ; Hongisto, Vesa ; Leivonen, Suvi ; Due, Eldri ; Tadele, Dagim ; Edgren, Henrik ; Kallioniemi, Olli ; Perälä, Merja ; Mælandsmo, Gunhild ; Sahlberg, Kristine. / Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response. In: Breast Cancer. 2017 ; Vol. 9. pp. 185-198.
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    title = "Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response",
    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.",
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    author = "Sandra Jernstr{\"o}m and Vesa Hongisto and Suvi Leivonen and Eldri Due and Dagim Tadele and Henrik Edgren and Olli Kallioniemi and Merja Per{\"a}l{\"a} and Gunhild M{\ae}landsmo and Kristine Sahlberg",
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    Jernström, S, Hongisto, V, Leivonen, S, Due, E, Tadele, D, Edgren, H, Kallioniemi, O, Perälä, M, Mælandsmo, G & Sahlberg, K 2017, 'Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response', Breast Cancer, vol. 9, A22, pp. 185-198. https://doi.org/10.2147/BCTT.S115600

    Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response. / Jernström, Sandra; Hongisto, Vesa; Leivonen, Suvi; Due, Eldri; Tadele, Dagim; Edgren, Henrik; Kallioniemi, Olli; Perälä, Merja; Mælandsmo, Gunhild; Sahlberg, Kristine.

    In: Breast Cancer, Vol. 9, A22, 21.03.2017, p. 185-198.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response

    AU - Jernström, Sandra

    AU - Hongisto, Vesa

    AU - Leivonen, Suvi

    AU - Due, Eldri

    AU - Tadele, Dagim

    AU - Edgren, Henrik

    AU - Kallioniemi, Olli

    AU - Perälä, Merja

    AU - Mælandsmo, Gunhild

    AU - Sahlberg, Kristine

    PY - 2017/3/21

    Y1 - 2017/3/21

    N2 - 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.

    AB - 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.

    KW - drug screening

    KW - ErbB2

    KW - gene expression

    KW - pharmacogenomics

    KW - predictors

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    U2 - 10.2147/BCTT.S115600

    DO - 10.2147/BCTT.S115600

    M3 - Article

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    EP - 198

    JO - Breast Cancer

    JF - Breast Cancer

    SN - 1179-1314

    M1 - A22

    ER -